Parenteral sparfloxacin compared with ceftriaxone in treatment of experimental endocarditis due to penicillin-susceptible and -resistant streptococci.

A new, investigational, parenteral form of sparfloxacin was compared with ceftriaxone in the treatment of experimental endocarditis caused by either of three penicillin-susceptible streptococci or one penicillin-resistant streptococcus. Both drugs have prolonged half-lives in serum, allowing single daily administration to humans. Sparfloxacin had relatively low MICs (0.25 to 0.5 mg/liter) for all four organisms and was also greater than or equal to eight times more effective than the other quinolones against 21 additional streptococcal isolates recovered from patients with bacteremia. Ceftriaxone MICs were 0.032 to 0.064 mg/liter for the penicillin-susceptible strains and 2 mg/liter for the resistant isolate. Both antibiotics resulted in moderate bacterial killing in vitro. Rats with catheter-induced aortic vegetations were inoculated with 10(7) CFU of the test organisms. Antibiotic treatment was started 48 h later and lasted either 3 or 5 days. The drugs were injected at doses which mimicked the kinetics in human serum produced by one intravenous injection of 400 mg of sparfloxacin (i.e., the daily dose expected to be given to human adults) and 2 g of ceftriaxone. Both antibiotics significantly decreased the bacterial densities in the vegetations. However, sparfloxacin was slower than ceftriaxone in its ability to eradicate valvular infection caused by penicillin-susceptible bacteria. While this difference was quite marked after 3 days of therapy, it tended to vanish when treatment was prolonged to 5 days. In contrast, sparfloxacin was very effective against the penicillin-resistant isolate, an organism against which ceftriaxone therapy failed in vivo. No sparfloxacin-resistant mutant was selected during therapy. Thus, in the present experimental setting, this new, investigational, parenteral form of sparfloxacin was effective against severe infections caused by both penicillin-susceptible and penicillin-resistant streptococci.

Therapeutic Drug Monitoring of the new targeted anticancer agents imatinib, nilotinib, dasatinib, sunitinib, sorafenib and lapatinib by LC tandem mass spectrometry.

The treatment of some cancer patients has shifted from traditional, non-specific cytotoxic chemotherapy to chronic treatment with molecular targeted therapies. Imatinib mesylate, a selective inhibitor of tyrosine kinases (TKIs) is the most prominent example of this new era and has opened the way to the development of several additional TKIs, including sunitinib, nilotinib, dasatinib, sorafenib and lapatinib, in the treatment of various hematological malignancies and solid tumors. All these agents are characterized by an important inter-individual pharmacokinetic variability, are at risk for drug interactions, and are not devoid of toxicity. Additionally, they are administered for prolonged periods, anticipating the careful monitoring of their plasma exposure via Therapeutic Drug Monitoring (TDM) to be an important component of patients' follow-up. We have developed a liquid chromatography-tandem mass spectrometry method (LC-MS/MS) requiring 100 microL of plasma for the simultaneous determination of the six major TKIs currently in use. Plasma is purified by protein precipitation and the supernatant is diluted in ammonium formate 20 mM (pH 4.0) 1:2. Reverse-phase chromatographic separation of TKIs is obtained using a gradient elution of 20 mM ammonium formate pH 2.2 and acetonitrile containing 1% formic acid, followed by rinsing and re-equilibration to the initial solvent composition up to 20 min. Analyte quantification, using matrix-matched calibration samples, is performed by electro-spray ionization-triple quadrupole mass spectrometry by selected reaction monitoring detection using the positive mode. The method was validated according to FDA recommendations, including assessment of extraction yield, matrix effects variability (<9.6%), overall process efficiency (87.1-104.2%), as well as TKIs short- and long-term stability in plasma. The method is precise (inter-day CV%: 1.3-9.4%), accurate (-9.2 to +9.9%) and sensitive (lower limits of quantification comprised between 1 and 10 ng/mL). This is the first broad-range LC-MS/MS assay covering the major currently in-use TKIs. It is an improvement over previous methods in terms of convenience (a single extraction procedure for six major TKIs, reducing significantly the analytical time), sensitivity, selectivity and throughput. It may contribute to filling the current knowledge gaps in the pharmacokinetics/pharmacodynamics relationships of the latest TKIs developed after imatinib and better define their therapeutic ranges in different patient populations in order to evaluate whether a systematic TDM-guided dose adjustment of these anticancer drugs could contribute to minimize the risk of major adverse reactions and to increase the probability of efficient, long lasting, therapeutic response.

Dose reduction of epoetin-alpha in the prevention of chemotherapy-induced anaemia.

INTRODUCTION: Anaemia during chemotherapy is often left untreated. Erythropoiesis-stimulating agents are frequently used to treat overt anaemia. Their prophylactic use, however, remains controversial and raises concerns about cost-effectiveness. Therefore, we assessed the efficacy of a dose-reduction schedule in anaemia prophylaxis. MATERIALS AND METHODS: The study included patients with untreated solid tumours about to receive platinum-based chemotherapy and had haemoglobin (Hb) levels ≥11 g/dL. Epoetin-α was administered at a dose level of 3 × 10,000 U weekly as soon as Hb descended to < 13 g/dL. Dose reductions to 3 × 4,000 U and 3 × 2,000 U weekly were planned in 4-week intervals if Hb stabilised in the range of 11-13 g/dL. Upon ascending to ≥13 g/dL, epoetin was discontinued. Iron supplements of 100 mg intravenous doses were given weekly. Of 37 patients who enrolled, 33 could be evaluated. RESULTS AND DISCUSSION: Their median Hb level was 13.7 (10.9-16.2) g/dL at baseline and descended to 11.0 (7.4-13.8) g/dL by the end of chemotherapy. Anaemia (Hb < 10 g/dL) was prevented in 24 patients (73%). The mean dose requirement for epoetin-α was 3 × 5,866 U per week per patient, representing a dose reduction of 41%. Treatment failed in nine patients (27%), in part due to epoetin-α resistance in four (12%) and blood transfusion in three (9%) patients. CONCLUSION: Dose reduction was as effective as fixed doses in anaemia prophylaxis but reduced the amount of prescribed epoetin substantially.

Gemcitabine, oxaliplatin and 5-FU in advanced bile duct and gallbladder carcinoma: two parallel, multicentre phase-II trials.

BACKGROUND: Gemcitabine, oxaliplatin and 5-fluorouracil (5-FU) are active in biliary tract cancer and have a potentially synergistic mode of action and non-overlapping toxicity. The objective of these trials was to determine response, survival and toxicity separately in patients with bile duct cancer (BDC) and gallbladder cancer (GBC) treated with gemcitabine/oxaliplatin/5-FU chemotherapy. METHODS: Eligible patients with histologically proven, advanced or metastatic BDC (n=37) or GBC (n=35) were treated with gemcitabine (900 mg m(-2) over 30 min), oxaliplatin (65 mg m(-2)) and 5-FU (1500 mg m(-2) over 24 h) on days 1 and 8 of a 21-day cycle. Tumour response was the primary outcome measure. RESULTS: Response rates were 19% (95% CI: 6-32%) and 23% (95% CI: 9-37%) for BDC and GBC, respectively. Median survivals were 10.0 months (95% CI: 8.6-12.4) and 9.9 months (95% CI: 7.5-12.2) for BDC and GBC, respectively, and 1- and 2-year survival rates were 40 and 23% in BDC and 34 and 6% in GBC (intention-to-treat analysis). Major grade III and IV adverse events were neutropenia, thrombocytopenia, elevated bilirubin and anorexia. CONCLUSION: Triple-drug chemotherapy achieves comparable results for response and survival to previously reported regimens, but with more toxicity.

Multicenter trial of neo-adjuvant chemotherapy followed by extrapleural pneumonectomy in malignant pleural mesothelioma.

BACKGROUND: The aim of this multicenter trial was to prospectively evaluate neo-adjuvant chemotherapy followed by extrapleural pneumonectomy (EPP) and radiotherapy, including quality of life as outcome. PATIENTS AND METHODS: Eligible patients had malignant pleural mesothelioma of all histological types, World Health Organization performance status of zero to two and clinical stage T1-T3, N0-2, M0 disease considered completely resectable. Neo-adjuvant chemotherapy consisted of three cycles of cisplatin and gemcitabine followed by EPP. Postoperative radiotherapy was considered for all patients. RESULTS: In all, 58 of 61 patients completed three cycles of neo-adjuvant chemotherapy. Forty-five patients (74%) underwent EPP and in 37 patients (61%) the resection was complete. Postoperative radiotherapy was initiated in 36 patients. The median survival of all patients was 19.8 months [95% confidence interval (CI) 14.6-24.5]. For the 45 patients undergoing EPP, the median survival was 23 months (95% CI 16.6-32.9). Psychological distress showed minor variations over time with distress above the cut-off score indicating no morbidity with 82% (N = 36) at baseline and 76% (N = 26) at 3 months after surgery (P = 0.5). CONCLUSIONS: The observed rate of operability is promising. A median survival of 23 months for patients undergoing EPP compares favourably with the survival reported from single center studies of upfront surgery. This approach was not associated with an increase in psychological distress.

Growing up in Ireland. Key findings: infant cohort (at 3 years).

 The latest results from the study paint a picture of how these families are faring across a range of areas in their lives including their health, family life and financial and economic circumstances. In general the findings show that three-year-olds in Ireland are in good health with a few notable public health and related issues (including overweight and obesity), there is overall stability in family structures over the short term and that the recession has had a substantial effect on families with young children over the last number of years. These are the first longitudinal findings from the study. The first wave of fieldwork with the families of the Infant Cohort included approximately 11,100 nine-month-olds, their parents and carers. Interviews began in September 2008 and were completed in March 2009. Interviews for the second round of interviews with this cohort took place between January and August 2011. A total of 90% of the original sample of nine-month-olds were successfully re-interviewed. (A full download of the results released today, presented in three briefing documents can be found by clicking here. Key findings include: Health â?¢ Most of the children were described as being in good health; 75% were rated as very healthy and a further 23% were rated as healthy, but a few minor problems. Girls were more likely to be reported as very healthy (78%) compared with boys (72%). â?¢ One in four or almost one quarter of three-year-old children were overweight (19%) or obese (6%). â?¢ Childrenâ?Ts weight was related to household social class. 5% of children in families in the professional/managerial group were classified as obese at three years of age compared with 9% of those in the most disadvantaged social class group. However, at least one-fifth of children in every social class were overweight. â?¢ Childrens consumption of energy-dense foods such as crisps, sweets, chips, and non-diet fizzy drinks increased as parental education fell. 63% of children whose mother had a lower secondary education or less ate at least one portion of crisps compared with 36% of those from degree-level backgrounds, although consumption of biscuits/chocolates was over 70% for both groups of children. â?¢ Two-thirds (66%) of three-year-olds had received at least one course of antibiotics in the 12 months preceding the interview. Children with a full medical card (35% of the sample) or a GP-only medical card (5% of the sample) were more likely to have received a course of antibiotics than â?¢ Children with a full medical card received a higher number of antibiotic courses on average (2.6) compared with those without a medical card (2.1). â?¢ Just under 16% of three-year-old children were reported as having at least one longstanding illness, condition or disability. The most commonly reported illness types included Asthma (5.8%), Eczema/Skin allergies (3.9%) and Food/digestive allergies (1.2%) Family Life and Childcare â?¢ While the overall distribution of family structure was stable, there have been transitions from one-parent families to two-parent families and vice-versa over the 27 months between interview â?" approximately 2 to 3 percent in each direction. â?¢ 50% of three year olds were in some form of non-parental childcare for eight or more hours a week. The most common form used was centre-based childcare which almost tripled between nine months and three years, from 11% to 30%. â?¢ A similar percentage of grandparents were caring for children at both nine months and three years, 12% and 11% respectively. A total of 10% of three-year-olds were being minded by a childminder, an increase of 3 percentage points from when the children were nine months of age. â?¢ Children who were in some form of non-parental childcare were spending an average of 23 hours a week in their main type of childcare. â?¢ At time of interview the vast majority of mothers reported that they had regular contact with the Study Childâ?Ts grandparents (91%). In offering support to parents, grandparents were most likely to babysit (50%), and buy clothes (40%) at least on a monthly basis. One-parent families were more likely than two-parent families to receive financial support from grandparents with just under one-third (66%) of one-parent families receiving financial support from grandparents at least once every three months. â?¢ The most frequently used discipline technique was â?~discussing or explaining why the behaviour was wrongâ?T, with 63% of mothers saying they always did this. â?¢ 12% of mothers said they used â?~smackingâ?T as a form of discipline now and again and less than 1% used â?~smackingâ?T as a form of discipline more frequently. Over half reported that they never smacked the Study Child. Financial and Economic Circumstances â?¢ Just over half (53%) of mothers of three-year-olds worked outside the home, 38% said they were on home duties and 6% said they were unemployed. â?¢ The biggest change in terms of the work status of three-year-oldsâ?T parents was an increase in the percentage of unemployed fathers â?" 6% when the child was nine months rising to almost 14% when s/he was three years of age. â?¢ 61% of families of three-year-olds reported experiencing difficulties in making â?~ends meetâ?T. This was a substantial increase from 44% in the first round of interviews when the children were nine-months-old. â?¢ Almost two thirds (63%) of all families with three-year-olds reported that the recession had had a very significant or significant effect on them. â?¢ The most frequently recorded effects were: a reduction in wages (63%); canâ?Tt afford luxuries (54%), social welfare reduction (53%) and canâ?Tt afford/cut back on basics (32%). Growing Up in Ireland is a Government funded study tracking the development of two nationally representative cohorts of children: an Infant Cohort which was interviewed initially at nine months and subsequently at three years of age; and a Child Cohort which was interviewed initially at nine years and subsequently at 13 years of age. The study is being conducted by a consortium of researchers led by the Economic and Social Research Institute (ESRI) and Trinity College Dublin. For Further Information Please Contact: Jillian Heffernan Communications Officer, Growing Up in Ireland Tel: 01 896 3378 Mobile: 087 9016880This resource was contributed to our repository by the National Documentation Centre on Drug Use.

Melan-A-specific cytotoxic T cells are associated with tumor regression and autoimmunity following treatment with anti-CTLA-4.

PURPOSE: Ipilimumab is a monoclonal antibody that blocks the immune-inhibitory interaction between CTL antigen 4 (CTLA-4) and its ligands on T cells. Clinical trials in cancer patients with ipilimumab have shown promising antitumor activity, particularly in patients with advanced melanoma. Often, tumor regressions in these patients are correlated with immune-related side effects such as dermatitis, enterocolitis, and hypophysitis. Although these reactions are believed to be immune-mediated, the antigenic targets for the cellular or humoral immune response are not known. EXPERIMENTAL DESIGN: We enrolled patients with advanced melanoma in a phase II study with ipilimumab. One of these patients experienced a complete remission of his tumor. The specificity and functional properties of CD8-positive T cells in his peripheral blood, in regressing tumor tissue, and at the site of an immune-mediated skin rash were investigated. RESULTS: Regressing tumor tissue was infiltrated with CD8-positive T cells, a high proportion of which were specific for Melan-A. The skin rash was similarly infiltrated with Melan-A-specific CD8-positive T cells, and a dramatic (>30-fold) increase in Melan-A-specific CD8-positive T cells was apparent in peripheral blood. These cells had an effector phenotype and lysed Melan-A-expressing tumor cells. CONCLUSIONS: Our results show that Melan-A may be a major target for both the autoimmune and antitumor reactions in patients treated with anti-CTLA-4, and describe for the first time the antigen specificity of CD8-positive T cells that mediate tumor rejection in a patient undergoing treatment with an anti-CTLA-4 antibody. These findings may allow a better integration of ipilimumab into other forms of immunotherapy.

Validation of hepcidin quantification in plasma using LC-HRMS and discovery of a new hepcidin isoform.

BACKGROUND: Hepcidin, a 25 amino acid peptide, plays an important role in iron homeostasis. Some hepcidin truncated peptides have antibiotic effects. RESULTS: A new analytical method for hepcidin determination in human plasma using LC-HRMS operating in full-scan acquisition mode has been validated. The extraction consists of protein precipitation and a drying reconstitution step; a 2.1 x 50 mm (idxL) C18 analytical column was used. Detection specificity, stability, accuracy, precision and recoveries were determined. The LOQ/LOD were 0.25/0.1 nM, respectively. More than 600 injections of plasma extracts were performed, allowing evaluation of the assay robustness. Hepcidin-20, hepcidin-22 and a new isoform, hepcidin-24, were detected in patients. CONCLUSION: The data underscore the usefulness of LC-HRMS for in-depth investigations related to hepcidin levels and pathways.

Cytostatic lung perfusion results in heterogeneous spatial regional blood flow and drug distribution: evaluation of different cytostatic lung perfusion techniques in a porcine model.

OBJECTIVES: Comparison of doxorubicin uptake, leakage and spatial regional blood flow, and drug distribution was made for antegrade, retrograde, combined antegrade and retrograde isolated lung perfusion, and pulmonary artery infusion by endovascular inflow occlusion (blood flow occlusion), as opposed to intravenous administration in a porcine model. METHODS: White pigs underwent single-pass lung perfusion with doxorubicin (320 mug/mL), labeled 99mTc-microspheres, and Indian ink. Visual assessment of the ink distribution and perfusion scintigraphy of the perfused lung was performed. 99mTc activity and doxorubicin levels were measured by gamma counting and high-performance liquid chromatography on 15 tissue samples from each perfused lung at predetermined localizations. RESULTS: Overall doxorubicin uptake in the perfused lung was significantly higher (P = .001) and the plasma concentration was significantly lower (P < .0001) after all isolated lung perfusion techniques, compared with intravenous administration, without differences between them. Pulmonary artery infusion (blood flow occlusion) showed an equally high doxorubicin uptake in the perfused lung but a higher systemic leakage than surgical isolated lung perfusion (P < .0001). The geometric coefficients of variation of the doxorubicin lung tissue levels were 175%, 279%, 226%, and 151% for antegrade, retrograde, combined antegrade and retrograde isolated lung perfusion, and pulmonary artery infusion by endovascular inflow occlusion (blood flow occlusion), respectively, compared with 51% for intravenous administration (P = .09). 99mTc activity measurements of the samples paralleled the doxorubicin level measurements, indicating a trend to a more heterogeneous spatial regional blood flow and drug distribution after isolated lung perfusion and blood flow occlusion compared with intravenous administration. CONCLUSIONS: Cytostatic lung perfusion results in a high overall doxorubicin uptake, which is, however, heterogeneously distributed within the perfused lung.

Candida colonization in intensive care unit patients' urine

The objective of this study was to identify possible predisposing factors for candiduria in intensive care unit (ICU) patients from Hospital das Clínicas, Universidade Federal de Goiás, Goiânia, Brazil, during one year. Urine samples from 153 ICU patients were obtained by catheterization on admission day and every seven days. Data such as sex, age, antifungal therapy, and variables as antibiotics, underlying diseases or comorbid conditions and stay in the hospital, were collected from patients who had at least one urine culture that yielded > 10³ yeast colonies/ml. Candiduria was recovered in 68 patients and the commonest predisposing factors were antibiotic therapy (100%) and indwelling urinary catheter (92.6%). The percentage of Candida spp. isolation increased during the extended periods in which patients remained in the ICU. C. albicans was isolated in 69.1%, and the other species non-albicans as C. glabrata, C. kefyr, C. parapsilosis, C. famata, C. guilliermondii, C. krusei, and C. tropicalis were isolated in lower percentage. The high frequency of candiduria and the possible predisposing factors found in ICU patients show that candiduria surveillance should be performed to help reducing nosocomial infections.

Serogroups, K1 antigen, and antimicrobial resistance patterns of Aeromonas spp. strains isolated from different sources in Mexico

A total of 221 strains of Aeromonas species isolated in Mexico from clinical (161), environmental (40), and food (20) samples were identified using the automated system bioMérieux-Vitek®. Antisera for serogroups O1 to 044 were tested using the Shimada and Sakazaki scheme. The K1 antigen was examined using as antiserum the O7:K1C of Escherichia coli. Besides, we studied the antimicrobial patterns according to Vitek AutoMicrobic system. Among the 161 clinical strains 60% were identified as A. hydrophila, 20.4% as A. caviae, and 19.25% as A. veronii biovar sobria. Only A. hydrophila and A. veronii biovar sobria were found in food (55 and 90% respectively) and environmental sources (45 and 10% respectively). Using "O" antisera, only 42.5% (94/221) of the strains were serologically identified, 55% (121/221) were non-typable, and 2.5% (6/221) were rough strains. Twenty-two different serogroups were found, O14, O16, O19, O22, and O34 represented 60% of the serotyped strains. More than 50% of Aeromonas strain examined (112/221) expressed K1 encapsulating antigen; this characteristic was predominant among Aeromonas strains of clinical origin. Resistance to ampicillin/sulbactam and cephazolin was detected in 100 and 67% of Aeromonas strain tested for their susceptibility to antibiotics. In conclusion, antibiotic-resistant Aeromonas species that possess the K1 encapsulating antigen and represent serogroups associated with clinical syndrome in man are not uncommon among Aeromonas strains isolated from clinical, food and environmental sources in Mexico.

PchC thioesterase optimizes nonribosomal biosynthesis of the peptide siderophore pyochelin in Pseudomonas aeruginosa.

In Pseudomonas aeruginosa, the antibiotic dihydroaeruginoate (Dha) and the siderophore pyochelin are produced from salicylate and cysteine by a thiotemplate mechanism involving the peptide synthetases PchE and PchF. A thioesterase encoded by the pchC gene was found to be necessary for maximal production of both Dha and pyochelin, but it was not required for Dha release from PchE and could not replace the thioesterase function specified by the C-terminal domain of PchF. In vitro, 2-aminobutyrate, a cysteine analog, was adenylated by purified PchE and PchF proteins. In vivo, this analog strongly interfered with Dha and pyochelin formation in a pchC deletion mutant but affected production of these metabolites only slightly in the wild type. Exogenously supplied cysteine overcame the negative effect of a pchC mutation to a large extent, whereas addition of salicylate did not. These data are in agreement with a role for PchC as an editing enzyme that removes wrongly charged molecules from the peptidyl carrier protein domains of PchE and PchF.

Northern Ireland Point Prevalence Survey of Hospital-acquired Infections and Antimicrobial Use 2012

The PHA�coordinated Northern Ireland's participation in ECDC's National Prevalence Survey on�Hospital-Acquired Infections & on Antimicrobial Use. Hospitals in Northern Ireland participated in data collection between May and June 2012.This report provides a snapshot of the levels of hospital-acquired infections (HAI) and levels of antimicrobial use (AMU) in hospitals in Northern Ireland during 2012.There have been three previous HAI PPS surveys and the last survey was carried out in 2006. It is difficult to compare each survey as the data was collected in a different way. However, after making allowances, there was an overall drop in HAI prevalence of 18% from 2006 to 2012.The PPS data collection was undertaken by hospital teams between May and June 2012 (one hospital deferred data collection until September 2012 because of a move to a new hospital); 16 hospitals surveyed 3,992 eligible patients. The median age of all patients was 66 years. A total of 383 (10 per cent) children under 16 years of age were surveyed.�Key results from this year's survey:The prevalence of HAI was 4.2%. A total of 166 patients were diagnosed with an active HAI with 3 patients having more than one infection.When comparing ward specialties, HAI prevalence was highest for patients in adult intensive care units (ICUs) at 9.1 per cent, followed by care of the elderly wards at 5.7%.The most common types of HCAI were respiratory infections (including pneumonia and infections of the lower respiratory tract) (27.9 per cent of all infections), surgical site infections (18.9 per cent) and urinary tract infections (UTI) (11.8 per cent).Since the last PPS in 2006 there has been a reduction in MRSA infections - from 0.9 per cent �of the hospital population to less than 0.1 per cent in patients; and a five-fold reduction in C. difficile infections (from 1.1 per cent to 0.2 per cent).The prevalence of antimicrobial use was 29.5%.Most antibiotic use (60 per cent) in hospitals was in patients receiving treatment for infections which commenced in the community. Eleven percent of surgical prophylaxis was prescribed for greater than one day.��