Characterization of coagulase-negative staphylococcal isolates from blood with reduced susceptibility to glycopeptides and therapeutic options

<p>Abstract</p> <p>Background</p> <p>Coagulase-negative staphylococci (CoNS) are a major cause of nosocomial blood stream infection, especially in critically ill and haematology patients. CoNS are usually multidrug-resistant and glycopeptide antibiotics have been to date considered the drugs of choice for treatment. The aim of this study was to characterize CoNS with reduced susceptibility to glycopeptides causing blood stream infection (BSI) in critically ill and haematology patients at the University Hospital Tor Vergata, Rome, Italy, in 2007.</p> <p>Methods</p> <p>Hospital microbiology records for transplant haematology and ICU were reviewed to identify CoNS with elevated MICs for glycopeptides, and isolates were matched to clinical records to determine whether the isolates caused a BSI. The isolates were tested for susceptibility to new drugs daptomicin and tigecycline and the genetic relationship was assessed using f-AFLP.</p> <p>Results</p> <p>Of a total of 17,418 blood cultures, 1,609 were positive for CoNS and of these, 87 (5.4%) displayed reduced susceptibility to glycopeptides. Clinical review revealed that in 13 cases (7 in haematology and 6 in ICU), CoNS with reduced susceptibility to glycopeptides were responsible for a BSI. <it>Staphylococcus epidermidis </it>was the causative organism in 11 instances and <it>Staphylococcus haemolyticus </it>in 2. The incidence of oxacillin resistance was high (77%), although all isolates remained susceptible to linezolid, daptomycin and tigecycline. Fingerprinting of CoNS identified one clonal relationship between two isolates.</p> <p>Conclusion</p> <p>Multi-resistant CoNS with reduced susceptibility to glycopeptides, although still relatively infrequent in our hospital, are emerging pathogens of clinical concern. Surveillance by antibiotyping with attention to multi-resistant profile, and warning to clinicians, is necessary.</p

Geminin Is Required for Zygotic Gene Expression at the Xenopus Mid-Blastula Transition

In many organisms early development is under control of the maternal genome and zygotic gene expression is delayed until the mid-blastula transition (MBT). As zygotic transcription initiates, cell cycle checkpoints become activated and the tempo of cell division slows. The mechanisms that activate zygotic transcription at the MBT are incompletely understood, but they are of interest because they may resemble mechanisms that cause stem cells to stop dividing and terminally differentiate. The unstable regulatory protein Geminin is thought to coordinate cell division with cell differentiation. Geminin is a bi-functional protein. It prevents a second round of DNA replication during S and G2 phase by binding and inhibiting the essential replication factor Cdt1. Geminin also binds and inhibits a number of transcription factors and chromatin remodeling proteins and is thought to keep dividing cells in an undifferentiated state. We previously found that the cells of Geminin-deficient Xenopus embryos arrest in G2 phase just after the MBT then disintegrate at the onset of gastrulation. Here we report that they also fail to express most zygotic genes. The gene expression defect is cell-autonomous and is reproduced by over-expressing Cdt1 or by incubating the embryos in hydroxyurea. Geminin deficient and hydroxyurea-treated blastomeres accumulate DNA damage in the form of double stranded breaks. Bypassing the Chk1 pathway overcomes the cell cycle arrest caused by Geminin depletion but does not restore zygotic gene expression. In fact, bypassing the Chk1 pathway by itself induces double stranded breaks and abolishes zygotic transcription. We did not find evidence that Geminin has a replication-independent effect on transcription. We conclude that Geminin is required to maintain genome integrity during the rapid cleavage divisions, and that DNA damage disrupts zygotic gene transcription at the MBT, probably through activation of DNA damage checkpoint pathways