Prolonged delay for controlling KPC-2-producing Klebsiella pneumoniae outbreak: the role of clinical management.

BACKGROUND: Carbapenemase-producing Enterobacteriaceae (CPE) are becoming of immediate concern for infection control policies. Prompt detection of CPE on health care setting admission is crucial to halt the spread of an outbreak. We report a cluster of 13 Klebsiella pneumoniae carbapenemase (KPC)-2-producing K pneumoniae cases in a tertiary care hospital.The objective of this study was to identify contributing factors originating the outbreak. METHODS: An outbreak investigation was conducted using descriptive epidemiology, observation of health care practices, and interviews of management staff. A root cause analysis was performed to identify patent and latent failures of infection control measures using the association of litigation and risk management method. RESULTS: The main patent failure was the delay in identifying KPC-2-producing K pneumoniae carriers. Contributing factors were work and environmental factors: understaffing, lack of predefined protocols, staff members' characteristics, and underlying patients' characteristics. Latent failures were as follows: no promotion of the national guidelines for prevention of CPE transmission, no clear procedure for the management of patients hospitalized abroad, no clear initiative for promoting a culture of quality in the hospital, biologic activity recently outsourced to a private laboratory, and poor communication among hospital members. CONCLUSION: Clinical management should be better promoted to control hospital outbreaks and should include team work and safety culture.

Probable nosocomial transmission of listeriosis in neonates.

Listeria monocytogenes was isolated in two neonates born consecutively in the same hospital in France. The isolates had indistinguishable pulsed-field electrophoresis profiles. Retrospective epidemiological investigations found no evidence of a food-borne or environmental source. Infection control protocols and decontamination processes were in accordance with standard recommendations. The timing of onset of these infections within the same maternity unit, and the similarity of pulsed-field gel electrophoresis profiles suggests cross-infection of L. monocytogenes between the two neonates.

A double-blind, randomized, placebo-controlled, parallel-group study of THC/CBD oromucosal spray in combination with the existing treatment regimen, in the relief of central neuropathic pain in patients with multiple sclerosis.

Central neuropathic pain (CNP) occurs in many multiple sclerosis (MS) patients. The provision of adequate pain relief to these patients can very difficult. Here we report the first phase III placebo-controlled study of the efficacy of the endocannabinoid system modulator delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray (USAN name, nabiximols; Sativex, GW Pharmaceuticals, Salisbury, Wiltshire, UK), to alleviate CNP. Patients who had failed to gain adequate analgesia from existing medication were treated with THC/CBD spray or placebo as an add-on treatment, in a double-blind manner, for 14 weeks to investigate the efficacy of the medication in MS-induced neuropathic pain. This parallel-group phase of the study was then followed by an 18-week randomized-withdrawal study (14-week open-label treatment period plus a double-blind 4-week randomized-withdrawal phase) to investigate time to treatment failure and show maintenance of efficacy. A total of 339 patients were randomized to phase A (167 received THC/CBD spray and 172 received placebo). Of those who completed phase A, 58 entered the randomized-withdrawal phase. The primary endpoint of responder analysis at the 30 % level at week 14 of phase A of the study was not met, with 50 % of patients on THC/CBD spray classed as responders at the 30 % level compared to 45 % of patients on placebo (p = 0.234). However, an interim analysis at week 10 showed a statistically significant treatment difference in favor of THC/CBD spray at this time point (p = 0.046). During the randomized-withdrawal phase, the primary endpoint of time to treatment failure was statistically significant in favor of THC/CBD spray, with 57 % of patients receiving placebo failing treatment versus 24 % of patients from the THC/CBD spray group (p = 0.04). The mean change from baseline in Pain Numerical Rating Scale (NRS) (p = 0.028) and sleep quality NRS (p = 0.015) scores, both secondary endpoints in phase B, were also statistically significant compared to placebo, with estimated treatment differences of -0.79 and 0.99 points, respectively, in favor of THC/CBD spray treatment. The results of the current investigation were equivocal, with conflicting findings in the two phases of the study. While there were a large proportion of responders to THC/CBD spray treatment during the phase A double-blind period, the primary endpoint was not met due to a similarly large number of placebo responders. In contrast, there was a marked effect in phase B of the study, with an increased time to treatment failure in the THC/CBD spray group compared to placebo. These findings suggest that further studies are required to explore the full potential of THC/CBD spray in these patients.

A randomized, double-blind, placebo-controlled, parallel-group, enriched-design study of nabiximols* (Sativex(®) ), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis.

BACKGROUND: Spasticity is a disabling complication of multiple sclerosis, affecting many patients with the condition. We report the first Phase 3 placebo-controlled study of an oral antispasticity agent to use an enriched study design. METHODS: A 19-week follow-up, multicentre, double-blind, randomized, placebo-controlled, parallel-group study in subjects with multiple sclerosis spasticity not fully relieved with current antispasticity therapy. Subjects were treated with nabiximols, as add-on therapy, in a single-blind manner for 4weeks, after which those achieving an improvement in spasticity of ≥20% progressed to a 12-week randomized, placebo-controlled phase. RESULTS: Of the 572 subjects enrolled, 272 achieved a ≥20% improvement after 4weeks of single-blind treatment, and 241 were randomized. The primary end-point was the difference between treatments in the mean spasticity Numeric Rating Scale (NRS) in the randomized, controlled phase of the study. Intention-to-treat (ITT) analysis showed a highly significant difference in favour of nabiximols (P=0.0002). Secondary end-points of responder analysis, Spasm Frequency Score, Sleep Disturbance NRS Patient, Carer and Clinician Global Impression of Change were all significant in favour of nabiximols. CONCLUSIONS: The enriched study design provides a method of determining the efficacy and safety of nabiximols in a way that more closely reflects proposed clinical practice, by limiting exposure to those patients who are likely to benefit from it. Hence, the difference between active and placebo should be a reflection of efficacy and safety in the population intended for treatment.

An ultrapure plasma-derived monoclonal antibody-purified factor IX concentrate (Nonafact®), results of phase III and IV clinical studies.

Nonafact(®), an ultrapure, monoclonal antibody-purified factor IX concentrate (FIX) was developed to minimize risk of thrombotic complications and viral transmission. To investigate the pharmacokinetics, efficacy and safety, phase III/IV studies were performed in the Netherlands and Poland from 1996 to 2007. The mean half-life, in vivo response and recovery of Nonafact(®) were 18.7 (SD 2.0) h, 1.1 (SD 0.2) IU dL(-1) per IU kg(-1) b.w. of FIX infused and 49% (SD 10%), respectively. Eleven surgical procedures were performed in eight patients. During two surgeries, both high-risk, blood loss was observed. No postoperative bleeding occurred. The in vivo recovery of FIX was higher than expected. In the phase III follow-up study, 26 previously treated patients (PTP) were included with a median follow-up of 1130 days. From the 1617 minor bleedings, 80.5% was stopped after a single infusion. In the phase IV study thirteen patients were treated for a median study period of 737 days. In the two follow-up studies the investigators rated the effect of Nonafact(®) as excellent/good in 95% of major bleedings. Surgeries for which Nonafact(®) was given prophylactically were without bleeding problems. In total more than 10 million units of Nonafact(®) were used during almost 120 person-years. Only one minor adverse event was reported. No inhibitors, viral transmissions and thrombogenic events occurred. In conclusion, Nonafact(®) is safe and provides excellent haemostasis in haemophilia B patients treated for spontaneous bleeding or undergoing surgical procedures. Due to the excellent in vivo recovery characteristic, treatment with Nonafact(®) is cost saving compared to other FIX products.

A double-blind, randomized, placebo-controlled, parallel-group study of Sativex, in subjects with symptoms of spasticity due to multiple sclerosis.

BACKGROUND: Muscle spasticity is common in multiple sclerosis (MS), occurring in more than 60% of patients. OBJECTIVE: To compare Sativex with placebo in relieving symptoms of spasticity due to MS. METHODS: A 15-week, multicenter, double-blind, randomized, placebo-controlled, parallel-group study in 337 subjects with MS spasticity not fully relieved with current anti-spasticity therapy. RESULTS: The primary endpoint was a spasticity 0-10 numeric rating scale (NRS). Intention-to-treat (ITT) analysis showed a non-significant improvement in NRS score, in favor of Sativex. The per protocol (PP) population (79% of subjects) change in NRS score and responder analyses (> or =30% improvement from baseline) were both significantly superior for Sativex, compared with placebo: -1.3 versus -0.8 points (change from baseline, p=0.035); and 36% versus 24% (responders, p=0.040). These were supported by the time to response (ITT: p=0.068; PP: p=0.025) analyses, carer global impression of change assessment (p=0.013) and timed 10-meter walk (p=0.042). Among the subjects who achieved a > or =30% response in spasticity with Sativex, 98, 94 and 73% reported improvements of 10, 20 and 30%, respectively, at least once during the first 4 weeks of treatment. Sativex was generally well tolerated, with most adverse events reported being mild-to-moderate in severity. DISCUSSION AND CONCLUSIONS: The 0-10 NRS and responder PP analyses demonstrated that Sativex treatment resulted in a significant reduction in treatment-resistant spasticity, in subjects with advanced MS and severe spasticity. The response observed within the first 4 weeks of treatment appears to be a useful aid to prediction of responder/non-responder status.

Randomized study of interferon beta-1a, low-dose azathioprine, and low-dose corticosteroids in multiple sclerosis.

BACKGROUND: Studies evaluating interferon beta (IFNbeta) for multiple sclerosis (MS) showed only partial efficacy. In many patients, IFNbeta does not halt relapses or disability progression. One strategy to potentially enhance efficacy is to combine IFNbeta with classical immunosuppressive agents, such as azathioprine (AZA) or corticosteroids, commonly used for other autoimmune disorders. OBJECTIVE: The Avonex-Steroids-Azathioprine study was placebo-controlled trial and evaluated efficacy of IFNbeta-1a alone and combined with low-dose AZA alone or low-dose AZA and low-dose corticosteroids as initial therapy. METHODS: A total of 181 patients with relapsing-remitting MS (RRMS) were randomized to receive IFNbeta-1a 30 microg intramuscularly (IM) once weekly, IFNbeta-1a 30 microg IM once weekly plus AZA 50 mg orally once daily, or IFNbeta-1a 30 microg IM once weekly plus AZA 50 mg orally once daily plus prednisone 10 mg orally every other day. The primary end point was annualized relapse rate (ARR) at 2 years. Patients were eligible for enrollment in a 3-year extension. RESULTS: At 2 years, adjusted ARR was 1.05 for IFNbeta-1a, 0.91 for IFNbeta-1a plus AZA, and 0.73 for combination. The cumulative probability of sustained disability progression was 16.8% for IFNbeta-1a, 20.7% for IFNbeta-1a plus AZA, and 17.5% for combination. There were no statistically significant differences among groups for either measure at 2 and 5 years. Percent T2 lesion volume change at 2 years was significantly lower for combination (+14.5%) versus IFNbeta-1a alone (+30.3%, P < 0.05). Groups had similar safety profiles. CONCLUSION: In IFNbeta-naïve patients with early active RRMS, combination treatment did not show superiority over IFNbeta-1a monotherapy.

Diagnosis of factor VIII deficiency.

The correct diagnosis of factor VIII deficiency and the assessment of severity of the disease are essential for a patient-tailored treatment strategy. An optimal diagnostic procedure comprises sensitive and specific screening methods and factor VIII activity assays. Different screening reagents show variable characteristics and receiver operator characteristic curves are presented showing the relation between sensitivity and specificity of eleven activated partial thromboplastin time reagents. The details of the three methods for factor VIII activity assay, one-stage and two-stage assay and chromogenic assays, are discussed. The chromogenic assay seems to be more sensitive than the one-stage assay with regard to the detection of severe haemophilia. Discrepant results obtained with one-stage and two-stage assays are reviewed and discussed.

Factor VIII genotype and inhibitor development in patients with haemophilia A: highest risk in patients with splice site mutations.

The appearance of inhibitory antibodies against factor VIII (FVIII) is the most severe and costly complication of replacement therapy in patients with haemophilia A (HA). To determine the relationship between FVIII genotype and inhibitor development, baseline FVIII activity, genotype and inhibitor development were reviewed in 1104 patients with HA. In patients with severe HA, splicing errors present the highest frequency of inhibitors, ahead of inversion of intron 1 and of intron 22, nonsense mutations and large deletions. The lowest inhibitor frequency in severe HA is found in patients with missense mutations and small deletions/insertions. Subanalyses indicate that nonsense mutations and small deletions/insertions leading to a frameshift in the light chain are associated with a significant higher risk of inhibitor formation than similar mutations occurring in the heavy chain (27% vs. 14%). These mutation types also have a higher frequency of inhibitors when occurring in exons 23-26, where a second FVIII transcript originates, compared with similar mutations in exons 1-22 (28% vs. 17%). These results suggest that complete absence of FVIII because of null mutations, including splice site mutations, or the absence of a second transcript result in an increased risk of inhibitor development.

The feasibility of total ankle prosthesis for severe arthropathy in haemophilia and prothrombin deficiency.

The standard treatment for end-stage arthropathy of the ankle joint in haemophilia has been fusion of the ankle joint. Total ankle replacement is used in osteoarthritis and especially in rheumatoid arthritis with good medium-term results. In this case series three patients are being described, in which a total of five total ankle replacements have been preformed. After a median follow up of 4.3 years (range 1-8.7) all prostheses were still in place and did not show any signs of loosening. Clinical scores showed a good to excellent result. In this small series total ankle replacement in patients with bleeding disorders show promising results. Further studies are needed to show the value of this relatively new type of surgery in haemophilic patients.

A clinical and cardiovascular survey of Ehlers-Danlos syndrome patients with complete deficiency of tenascin-X.

BACKGROUND: We recently described a new autosomal recessive type of Ehlers-Danlos syndrome (EDS) based on a deficiency of the extracellular matrix protein tenascin-X (TNX). TNX-deficient patients have hypermobile joints, hyperextensible skin and show easy bruising. Because of the reported cardiovascular abnormalities in other EDS types and the excessive haematoma formation after mild trauma in TNX-deficient individuals, we investigated whether cardiovascular or coagulation abnormalities occur in these patients. METHODS: We examined seven TNX-deficient patients. One of them had a mitral valve prolapse and died postoperatively after valve replacement, before the study was completed. RESULTS: Bleeding time and coagulation factors (INR, APTT, PT and fibrinogen) were all within the normal range. Ultrasonographic examination of the carotid and femoral arteries showed normal vessel wall compliance and distensibility. Echocardiography showed a slight billowing of the mitral valve in two patients from one family. All patients had normal diameters of aortic root and ascending aorta. CONCLUSION: Although the patient group is small, there are no indications of generalised cardiovascular abnormalities in this type of EDS. We would recommend echocardiography for all these patients at the first evaluation and when a cardiac murmur appears.

[Thrombophilia and the prevention of thromboembolic complications during pregnancy and the puerperium]. / Trombofilie en preventie van trombo-embolische complicaties tijdens zwangerschap en kraambed.

Deep vein thrombosis is one of the main causes of maternal death in the Western world, pulmonary embolism, as a complication, being the immediate cause of death in most cases. Deep vein thrombosis is the end result of several, partly interrelated, inherited and acquired risk factors. Thrombophilia is the overall name for a number of specific abnormalities resulting in an increased tendency towards haemocoagulation. In order to reduce the morbidity and mortality caused by thromboembolic complications in pregnant women, all women who want to become pregnant should be screened for risk factors in order to assess the a priori risk of venous thrombosis. Based on the individual thrombosis history and the presence of thrombophilia, a prophylactic policy can be determined for every pregnant woman. Currently, there are no data available from prospective and randomised trials assessing the effects of anticoagulants in pregnant women with thrombophilia.

In vivo recovery and safety of human factor VIII product AAFACT in patients with haemophilia A.

AAFACT, a monoclonal purified, solvent/detergent treated human plasma-derived coagulation factor VIII concentrate obtained from plasma of voluntary, non-remunerated blood donors, is manufactured and marketed in the Netherlands by Sanquin Plasma Products since 1995. In a postmarketing surveillance study, 70 previously treated haemophilia A patients were included (73% severe, 14% moderate and 13% mild haemophilia A). Most of these patients were followed during 4 years for the appearance of adverse events, possible transmissions of blood-borne viruses and the occurrence of antibodies against FVIII. The efficacy of treatment was determined in each patient by the in vivo recovery of FVIII. During this study, only six adverse events, possibly related to the use of AAFACT, were reported. None of these were indicated as serious. Transmissions of HIV, HAV, HBV and HCV in the seronegative patients have not been observed. In none of the patients, inhibitors to FVIII were detected. The in vivo recovery of FVIII during this study was not different from the in vivo recovery observed in eight patients during the preregistration study. There was a correlation of in vivo recovery with age and body weight. From these results, we conclude that the clinical usage of this human plasma-derived FVIII product is efficient and safe.

Prevention of symptomatic thrombosis with short term (low molecular weight) heparin in patients with rheumatoid arthritis after hip or knee replacement.

The need for prevention of venous thromboembolism (VTE) after total hip or knee replacement is obvious. However, the optimal regimen to achieve this remains to be defined. In patients with rheumatoid arthritis (RA) long term coumarins may not be necessary owing to the use of non-steroidal anti-inflammatory drugs (NSAIDs). 103 patients in whom 151 surgical procedures were performed (55 hip and 96 knee prostheses) were treated only with short term subcutaneous heparin. NSAIDs were used daily in 85% of the patients, and they were continued after hospital discharge. Only one patient developed symptomatic deep venous thrombosis during one year follow up. Bleeding complications were seen in 20/151 (13%) of the surgical procedures, all clinically judged as minor, and recovery was not delayed except in one case. Short term (low molecular weight) heparin appears to be an adequate, simple, and safe method for prevention of symptomatic VTE in patients with RA after knee or hip replacement, though further studies are necessary to confirm these preliminary findings.

Fibrinogen binding to the integrin alpha(IIb)beta(3) modulates store-mediated calcium entry in human platelets.

Effects of the occupation of integrin alpha(IIb)beta(3) by fibrinogen on Ca(++) signaling in fura-2-loaded human platelets were investigated. Adding fibrinogen to washed platelet suspensions inhibited increases in cytosolic [Ca(++)] concentrations ([Ca(++)](i)) evoked by adenosine diphosphate (ADP) and thrombin in a concentration-dependent manner in the presence of external Ca(++) but not in the absence of external Ca(++) or in the presence of the nonselective cation channel blocker SKF96365, indicating selective inhibition of Ca(++) entry. Fibrinogen also inhibited store-mediated Ca(++) entry (SMCE) activated after Ca(++) store depletion using thapsigargin. The inhibitory effect of fibrinogen was reversed if fibrinogen binding to alpha(IIb)beta(3) was blocked using RDGS or abciximab and was absent in platelets from patients homozygous for Glanzmann thrombasthenia. Fibrinogen was without effect on SMCE once activated. Activation of SMCE in platelets occurs through conformational coupling between the intracellular stores and the plasma membrane and requires remodeling of the actin cytoskeleton. Fibrinogen inhibited actin polymerization evoked by ADP or thapsigargin in control cells and in cells loaded with the Ca(++) chelator dimethyl BAPTA. It also inhibited the translocation of the tyrosine kinase p60(src) to the cytoskeleton. These results indicate that the binding of fibrinogen to integrin alpha(IIb)beta(3) inhibits the activation of SMCE in platelets by a mechanism that may involve modulation of the reorganization of the actin cytoskeleton and the cytoskeletal association of p60(src). This action may be important in intrinsic negative feedback to prevent the further activation of platelets subjected.

The type of factor VIII deficient plasma used influences the performance of the Nijmegen modification of the Bethesda assay for factor VIII inhibitors.

We have investigated the influence of the type of factor VIII deficient plasma used on the assay results of the Nijmegen modification of the Bethesda method for factor VIII inhibitors. Immuno depleted factor VIII deficient plasmas, lacking besides factor VIII also von Willebrand factor, gave decreased inhibitor titres compared to assay results with factor VIII deficient plasmas containing von Willebrand factor suggesting the need of the latter in the test system for the stability of factor VIII:C. Moreover the performance of the assay with immuno depleted plasma was contaminated in a certain type of this plasma by the presence of a factor VIII:C inhibitor. Chemically depleted factor VIII deficient plasma appeared to give falsely elevated titres when used in combination with other types of deficient plasmas as substrate plasma in the factor VIII:C assay due to the presence of activated factor Va in the preparation. Suggestions are described with respect to the observed limitations in order to obtain reliable results.

[Meningeal carcinomatosis as the first manifestation of gastric adenocarcinoma]. / Karcinóza mening jako první projev adenokarcinomu zaludku.

Gastric adenocarcinoma is rarely observed in patients under the age of 40. Meningeal carcinomatosis as a first manifestation of disease is absolutely unique. If meningeal involvement occurs it is usually secondary event in previously diagnosed tumor. The prognosis is very unfavorable associated with short term survival. In the treatment of this disease there night be used either chemotherapy administered via lumbar injection or radiotherapy or combination of both. This case study is one of very few cases reported in literature when meningeal carcinomatosis was a first sign of advanced gastric adenocarcinoma. 39 years old woman was admitted to our hospital with severe headache, diplopia and vomiting. Meningeal carcinomatosis with gastric primary was diagnosed. She was treated with combination of cytosine arabinosid (Cytosar), methotrexate (Methotrexat), hydrocortisone (Hydrocortisone) administered via intrathecal lumbar injection and whole brain radiation. As a main complication she experienced disseminated intravascular coagulopathy. The improvement of patient's condition following the initial treatment had a very limited duration and the patient died of bilateral pneumonia and cerebral edema 44th day after the admission.