BackgroundSince the release of linezolid vancomycin has been downgraded as an alternative in the treatment of central nervous system (CNS) infections caused by Gram-positive bacteria on account of its bad penetration and high incidence of nephrotoxicity. There are no studies with enough patients to support this trend.PurposeTo evaluate the efficacy and safety of vancomycin in CNS infections, and the impact of monitoring its pharmacokinetics.Material and methodsDescriptive retrospective study which included all patients with CNS infections treated with vancomycin and monitored. Patients aged under 18 and those who received less than 5 days’ treatment with vancomycin were excluded.ResultsA total of 62 patients were included, 39 with previous surgical intervention (SI) in the CNS.The most common diagnoses in the group with prior SI were bacterial meningitis (51%), fistula of cerebrospinal fluid (CSF) (21%) and shunt infection (21%). All had baseline neurological disease – neoplasms (46.2%) and subarachnoid haemorrhage (25.6%).Most patients without prior SI (n = 23) were diagnosed with bacterial meningitis (n = 21) and just 2 with a brain abscess. The infective pathogen was isolated in 39 samples of CSF. All isolated microorganisms were sensitive to vancomycin. 63.7% of the isolated microorganisms were coagulase-negative Staphylococcus, with a MIC = 2 in 23.7%.The initial and adjusted mean doses of vancomycin were 35.6 ± 9.3 mg/kg/day and 39.9 ± 15.2 mg/kg/day respectively. The median initial and adjusted Cmin were 10.04 (6.16) mcg/ml and 14.67 (3.66) mcg/ml respectively.Laboratory-confirmed CSF clearance was obtained in 26 of the 39 isolates, 73.1% during the first 10 days of treatment.The overall mortality was 5.8%, but only one death was related to the CNS infection.Although Cmin above 20 mcg/ml was recorded in 15 patients, none developed nephrotoxicity.ConclusionVancomycin is still an agent of choice for CNS infections. Vancomycin trough concentrations of 15–20 mcg/ml are recommended to achieve clinical effectiveness for CNS infections without causing nephrotoxicity.References and/or acknowledgementsNo conflict of interest.

BackgroundIntrathecal administration of methotrexate (MTX) in the treatment of different neoplastic diseases to prevent relapses in the CNS and the need to keep MTX concentrations in CSF during infusion of MTX requires study of the pharmacokinetics of MTX at this level. It is therefore necessary to measure concentrations of MTX in CSF.PurposeTo evaluate the validity (selectivity, accuracy and precision) of MTX measurements in CSF using a chemiluminescence assay for determination of MTX in plasma and to discard the matrix effect which might occur when measuring MTX in CSF.Material and methodsDifferent concentrations of MTX were tested in different types of samples to evaluate the selectivity and discard the matrix effect. To the studied matrix (CSF) were added increasing and known amounts of plasma with MTX (addition standard) and the results were correlated with the regression equation of the data obtained in both matrices. Accuracy was obtained by comparing the results of both matrices and obtaining the relative error. Due to the limitation of the small volume of CSF obtained in each extraction we were unable to perform different analyses on the same sample of CSF. 10 measurements on the same CSF sample containing a known quantity of MTX (obtained in our own test control) to evaluate precision were performed.ResultsFactor analysis of standard additions gave the regression line X=0.00233+1.0105Y. The correlation coefficient was r = 0.99 and the relative error was -2.3%. The series of 10 repetitions of CSF with a known concentration (436 μM) gave an average value of 445.44 μM (424–464 μM), with SD of 12.5 and a variation coefficient of 2.8%.ConclusionThe good selectivity, accuracy and precision of the CFS analysis by CMIA (Architect) gave reliable data on concentrations of MTX in CSF, highlighting the absence of the matrix effect.No conflict of interest.

BackgroundThe increasing incidence of carbapenem-resistant Klebsiella pneumoniae (CR-KP) has become a significant problem and treatment of infections caused by these pathogens is a major challenge for clinicians.PurposeTo describe infections caused by CR-KP in the setting of a single tertiary Spanish hospital outbreak between June 2012 and February 2013.Material and methodsEighty-one patients with confirmed KPC-producing isolates were included. Demographic and clinical records, antibiotic use and patient outcomes were collected retrospectively.ResultsEighty-one patients with confirmed CR-KP-producing isolates were included. Post-antibiogram treatment data were collected from 69 patients. The most used antibiotics were tigecycline (n = 44, 63.8%), gentamicin (n = 36, 52.2%), meropenem (n = 13, 18.8%), fosfomycin (n = 11, 15.9%) and colistin (n = 8, 11.6%). In 28 patients (40.6%) the regimen consisted of a single drug. Most patients (n = 41, 59.4%) received ≥2 drugs against the CR-KP isolate. The most common combination was tigecycline plus gentamicin, which was used in a total of 23 cases, alone (n = 19), or with a third drug (n = 4).The most active agent against CR-KP was tigecycline (72.8% susceptibility). Resistance rates to gentamicin, fosfomycin and colistin were 64.2%, 82.7% and 93.8%, respectively.The mean initial dose of gentamicin was 4.1 ± 1.4 mg/kg/day with a mean Cmax = 10.7 ± 5.6 mcg/ml and mean Cmin = 0.9 ± 1.3 mcg/ml. The pharmacokinetic monitoring of gentamicin allowed the mean daily dose to be increased to 5.5 ± 1.2 mg/kg reaching a mean Cmax = 16.5 ± 2.7 mcg/ml and mean Cmin = 0.6 ± 0.4 mcg/ml.We recorded a clinical cure or improvement in 44 patients (54.3%) and microbiological cure in 14 patients (17.3%). The overall mortality of the 81 patients was 27.2%, but just 13.6% of deaths were considered attributable to infection.ConclusionTo our knowledge this is the largest reported series of infections caused by CR-KP in the setting of a single-centre outbreak with such high levels of resistance and provides further input on the clinical management of this type of infection.References and/or AcknowledgementsNo conflict of interest.

plaque psoriasis (MS-PP) has occurred. In our country, the prescription of ustekinumab has increased greatly since its approval in 2009. Therefore, it is now time to reflect on its use and to assess the real world setting, before the arrival of newly approved drugs. Aim and objectives The primary end point was to assess drug survival for ustekinumab for MS-PP treatment. The secondary end point was to assess the effectiveness of ustekinumab for MS-PP treatment. Material and methods A retrospective observational study was conducted. All patients who had started treatment with ustekinumab for MS-PP from January 2009 to December 2017 were included. Data collected were demographics, line of biological treatment, dates for therapy start and discontinuation, reason for discontinuation, intensification, optimisation, and psoriasis area severity index (PASI) before starting ustekinumab and at weeks 24, 52 and at the last evaluation available. Drug survival was analysed using Kaplan-Meier plots and effectiveness was evaluated by PASI50, 75, 90 and 100. Subsequently, data were analysed with SPSS21. Results A total of 130 patients were included, 64.6% men, with a mean age of 44.4 (11-83) years. Treatment line of ustekinumab: firstline 65.4%, secondline 23.1%, third and subsequent lines, 11.5%. Intensification and optimisation was performed in 59.2% and 53.1%, respectively. Mean drug survival was 6.7 years (95% CI 6.06-7.42). Effectiveness was calculated for 101 patients because of lack of data. Mean PASI at the start was 11.3 (SD 6.8). At week 24, the relation of PASI 50/75/90/100 achieved was 74.3%/67.3%/56.4%/45.5%, respectively (no data available for 11patients). At week 52, the relation of PASI 50/75/90/100 achieved was 90.0%/75.0%/62.5%/51.3%, respectively (no data available for 21patients). At the end of the study, 84 patients continued treatment with ustekinumab and their mean PASI at that time was 1.2 (SD 2.3). Reasons for discontinuation were drug failure in 20.8%, no reason described in 7.7%, improvement in 3.1%, neoplasms in 2.3%, intolerance in 0.8% and patient preference in 0.8%. Conclusion and relevance The PHOENIX trials opened the window to PASI90 and we have confirmed the effectiveness of ustekinumab in real life. Furthermore, the results reported here indicated that this effectiveness persisted for a long time, as recently reported data by Salgüero-Fernandez. Therefore, this fact should be an unbiased factor to consider before changing psoriasis therapy to newer drugs based on our long term data.

BackgroundThe use of intrathecal (IT) methotrexate (MTX) in combination with systemic high dose MTX (HDMTX) is an established procedure for CNS prophylaxis in patients with acute lymphoblastic leukaemia (ALL), but the evidence for the necessity of this combination is not conclusive. An MTX concentration of 1 μM is assumed to be the lowest concentration for an antileukaemic effect.PurposeTo determine the rate of sufficient CSF MTX concentrations (1 μM) in paediatric patients with ALL who received HDMTX, to evaluate the suitability of IT MTX and to correlate MTX plasma and CSF concentrations.Material and methodsA retrospective observational study was conducted between April 2015 and September 2016. We included children up to 18 years with ALL who received 5000 mg/m² over 24 hours in accordance with LAL-SEHOP-PETHEMA-2013 protocols. CSF samples were obtained 18 hours (16–20 hours) after starting the HDMTX infusion and immediately before IT administration of MTX. Plasma samples were obtained at 2, 12, 23, 36, 42 and 60 hours after the start of infusion. CFS samples and plasma MTX at 12 hours were correlated by Spearman’s correlation. MTX was measured by architect chemiluminescence immunoassay.1 ResultsWe included 12 children, aged 2–16 years (7±3.6) who received 36 cycles of MTX. Patients received 5000 mg/m² over 24 hours; one child received 3000 mg/m² was included. MTX plasma levels at 12 hours and CSF concentrations were highly variable, ranging from 48.8 to 179.0 μM (median 72.2μM) and from 0.85 to 2.9 μM (median 1.4 μM), respectively. An MTX concentration above 1μM was found in 33 of 36 CSF samples (91.7%). The patient who received 3000 mg/m² (2 cycles) showed a lower CSF MTX concentration (0.83 and 1.08μM), corresponding to a lower plasma MTX concentration (54.37 and 60.88 μM). The correlation between plasma levels at 12 hours and CSF MTX concentrations was moderate–high (Spearman rank order correlation, r=0.71; p<0.01).ConclusionA potentially antileukaemic MTX concentration of 1 μM was obtained in CSF during the majority of MTX infusions (5000 mg/m2 over 24 hours).References and/or acknowledgements1. Montejano-Hervás P, et al. PKP-034. Determination of methotrexate in CSF by chemiluminescence using the architect. Eur J Hosp Pharm2016;23:A193–4.No conflict of interest