P.J. van den Broek

Anti-infective-treated central venous catheters: a systematic review of randomized controlled trials

ObjectiveThis systematic review assesses the effect of anti-infective-treated central venous catheters (CVCs) on catheter-related bloodstream infection (CRBSI) in the acute care setting.MethodsRandomized controlled trials were retrieved from Medline and the Cochrane Library up to 15xa0January 2007. Two reviewers independently assessed trial quality and extracted data. Data for CRBSI were combined where appropriate, using axa0random effects model. The impact of the risk for CRBSI in the control group (baseline risk) on the benefit of anti-infective CVCs was studied by using meta-regression based on the binomial normal bivariate meta-analysis model.ResultsTwenty-one trials were included in the review. Mainly intensive care (IC) patients were studied. Eighteen trials showed that anti-infective CVCs reduced the risk of CRBSI. The number needed to treat (NNT) varied from 182 toxa012, with baseline risks ranging fromxa01% toxa010%. Nearly all trials had serious methodological shortcomings. Three trials comparing minocycline-rifampicin-treated catheters with antiseptic-treated catheters showed inconsistent results. One trial suggested that there is not any difference in CRBSI between heparin- and antiseptic-treated CVCs.ConclusionBecause the NNT is large when the baseline risk is low, the use of anti-infective-treated CVCs in the acute care setting should only be considered in situations in which background rates of CRBSI are high. The magnitude of benefit as calculated in this review should be interpreted with caution because of strong arguments in favor of axa0systematic overestimation of the effect. Which type of anti-infective catheter is most effective could not be established from the available data.

Anti-infective-treated central venous catheters for total parenteral nutrition or chemotherapy: a systematic review

This systematic review assesses the effect of anti-infective-treated central venous catheters (CVCs) on catheter-related bloodstream infection (CRBSI) in patients who received a CVC for total parenteral nutrition (TPN) or chemotherapy. Randomised controlled trials were retrieved from Medline and the Cochrane Library up to 14 October 2007. Two reviewers independently assessed trial quality and extracted data. Data for CRBSI were combined where appropriate, using a random effects model, and subgroup meta-analysis was carried out where applicable. The impact of the risk for CRBSI in the control group on the effect of anti-infective CVCs was studied by using meta-regression based on the bivariate meta-analysis model. Nine trials were included in the review. One trial showed that antibiotic-treated CVCs reduced the risk for CRBSI in outpatients with chemotherapy and a CVC in-situ during a period of about nine weeks. Eight trials did not find an overall significant benefit in favour of antiseptic-treated CVCs in patients who had a CVC during a mean of about two weeks. No relationship could be established between the effect of anti-infective-treated CVCs and the underlying risk for CRBSI, although nearly all trials had serious methodological shortcomings. Thus, available scientific evidence to prevent CRBSI by the use of anti-infective-treated CVCs in patients receiving chemotherapy or TPN is not sufficient as a basis to recommend their use. The recommendation of the Centers for Disease Control and Prevention to use antibiotic- or antiseptic-impregnated CVCs, when the risk for CRBSI remains high despite good hygienic practice, should therefore be limited to patients in the intensive care/perioperative setting.

Critical amino-terminal segments in insertion of rat liver cytochrome P450 3A1 into the endoplasmic reticulum membrane

An in vitro transcription-translation assay was used to study the membrane topology of rat liver cytochrome P450 3A1. N-terminus deletion mutants were constructed to assess the importance of N-terminal regions in the stable incorporation of the protein into the microsomal membranes. Wild-type nascent cytochrome P450 bound to microsomes as an integral membrane protein through its hydrophobic N-terminal segments, uncleaved by signal peptidase. Deletion of the most N-terminal hydrophobic segment (positions 7–26) had a dramatic effect on endoplasmic reticulum membrane integration. Confirming the essential role of this stretch in P450 3A1 membrane targeting, proteolysis-resistant membrane-associated peptides were observed in all the in vitro translated mutants containing that segment. It is concluded that the membrane topogenesis of P450 3A1 is determined mainly by the amino-terminal hydrophobic segment.

Genetic and antigenic structural characterization for resistance of echovirus 11 to pleconaril in an immunocompromised patient.

Pleconaril is a capsid inhibitor used previously to treat enterovirus infections. A pleconaril-resistant echovirus 11 (E11) strain was identified before pleconaril treatment was given in an immunocompromised patient. The patient was also treated with intravenous Ig (IVIg) for a long period but remained unresponsive. The pleconaril-resistant strains could not be neutralized in vitro, confirming IVIg treatment failure. To identify the basis of pleconaril resistance, genetic and structural analyses were conducted. Analysis of a modelled viral capsid indicated conformational changes in the hydrophobic pocket that could prevent pleconaril docking. Substitutions (V117I, V119M and I188L) in the pleconaril-resistant viruses were found in the pocket region of VP1. Modelling suggested that V119M could confer resistance, most probably due to the protruding sulfate side chain of methionine. Although pleconaril resistance induced in vitro in a susceptible E11 clinical isolate was characterized by a different substitution (I183M), resistance was suggested to also result from a similar mechanism, i.e. due to a protruding sulfate side chain of methionine. Our results showed that resistant strains that arise in vivo display different markers from those identified in vitro and suggest that multiple factors may play a role in pleconaril resistance in patient strains. Based on IVIg treatment failure, we predict that one of these factors could be immune related. Thus, both IVIg and capsid inhibitors target the viral capsid and can induce mutations that can be cross-reactive, enabling escape from both IVIg and the drug. This could limit treatment options and should be investigated further.

Multifactorial origin of high incidence of Serratia marcescens in a cardio-thoracic ICU: Analysis of risk factors and epidemiological characteristics

OBJECTIVEnA four-fold increase in the incidence of Serratia marcescens occurred in a cardio-thoracic ICU within a 13-month period. Clinical, epidemiological and molecular characteristics were analysed to elucidate the outbreaks origin.nnnMETHODSnEpidemiological data were analysed by mapping clustered cases; isolates were genotyped by AFLP analysis. A case-control study was performed to identify risk factors for the acquisition of S. marcescens. Data were obtained from files and electronic databases of the ICU and Department of Medical Microbiology. The adherence to hygiene protocols on the ICU was reviewed by a medical audit.nnnRESULTSnGenotyping showed 16 distinct S. marcescens strains. Twenty-one cases and 39 controls were enrolled in the case-control study. Significant differences found by univariate analysis included the duration of surgery, APACHE-II-score on ICU admission, length of ICU stay, duration of mechanical ventilation, tube feeding and the sum of the number of days per invasive device. In a multivariate logistic regression model, the length of ICU stay and tube feeding were independent risk factors. Outbreak strains were not more frequently resistant to gentamicin, ciprofloxacin, meropenem or trimethoprim-sulfamethoxazole as compared to a reference group. Hygiene protocols, including hand washing, were insufficiently practiced by the ICUs medical staff.nnnCONCLUSIONSnThe heterogeneity of the strains points to transmission from various sources. This outbreak of S. marcescens was most probably caused by reduced hand washing and other breaks in infection prevention protocols in combination with the presence of the identified risk factors, which act by affecting the number and intensity of potential transmission events.

The ascorbate: ascorbate free radical oxidoreductase from the erythrocyte membrane is not cytochrome b561.

SummaryErythrocytes contain a plasma membrane redox system that can reduce extracellular ascorbate radicals by using intracellular ascorbate as an electron donor. In this study, the hypothesis was tested that cytochromeb561 was a component of this system. Spectroscopic analysis of erythrocyte membrane preparations revealed the presence of cytochromeb5 and hemoglobin but also of a cytochrome with properties similar to cytochromeb561, reducible by ascorbate and insensitive to CO. The presence of cytochromeb561 was studied further by reverse transcriptase-PCR analysis of erythrocyte progenitor cells, reticulocytes. However, no cytochromeb561 mRNA could be found. These results were corroborated by Western blot analysis with an anti-cytochromeb561 serum. No cytochromeb561 protein could be detected in extracts of erythrocyte membranes. It is therefore concluded that erythrocytes do not contain cytochromeb561 in their membranes. The possible involvement of other b-cytochromes in ascorbate-ascorbate free radical oxidoreductase activity is discussed.

National guidelines for infection control in The Netherlands

National guidelines for the prevention of hospital infections in The Netherlands were established by the Working Group on Infection Prevention (WIP) in 1981. Since 1992 these guidelines have functioned as national standards for infection control applicable in all hospitals. The organization of the WIP, the process of developing guidelines and the current guidelines are described. The working group has also produced guidelines for nursing homes, institutions for the mentally handicapped and dentists.

Transient and constitutive repression of cytoplasmic translation signaling in cells with mtDNA mutation

Abstract.Cytoplasmic translation is under sophisticated control but how cells adapt its rate to constitutive loss of mitochondrial oxidative phosphorylation is unknown. Here we show that translation is repressed in cells with the pathogenic A3243G mtDNA mutation or in mtDNA-less ρ0 cells by at least two distinct pathways, one transiently targeting elongation factor eEF-2 and the other initiation factor eIF-2α constitutively. Under conditions of exponential cell growth and mammalian target of rapamycin (mTOR) activation, eEF-2 becomes transiently phosphorylated by an AMP-activated protein kinase (AMPK)-dependent pathway, especially high in mutant cells. Independent of AMPK and mTOR, eIF-2α is constitutively phosphorylated in mutant cells, likely a signature of endoplasmic reticulum (ER)-stress response induced by the loss of oxidative phosphorylation. While the AMPK/eEF-2K/eEF-2 pathway appears to function in adaptation to physiological fluctuations in ATP levels in the mutant cells, the ER stress signified by constitutive protein synthesis inhibition through eIF-2α-mediated repression of translation initiation may have pathobiochemical consequences.