Safety and Efficacy of Rivaroxaban for Extended-Phase Anticoagulation of Patients with Unprovoked or Recurrent Venous Thromboembolism: Real-Life Data from the MAC Project.

Venous thromboembolism (VTE) is a major cause of death in the world. After the acute-phase treatment, the optimal duration of anticoagulation is still debatable. The latest guidelines suggest maintaining long-term anticoagulation in patients with cancer-associated thrombosis (CAT) or with unprovoked VTE and a low bleeding risk. Methods: The MAC Project is an ongoing prospective-cohort, multi-center, observational study in Italy. The project aims to collect real-life clinical information in unselected patients given oral anticoagulants for VTE over a 5-year follow-up period. There were no exclusion criteria, except for life expectancy <6 months and refusal to sign the informed consent form or to attend the planned follow-up visit. All patients were followed-up prospectively with clinical controls scheduled at 3, 6, and 12 months after the index event, and then annually for up to 5 years. The primary efficacy and safety outcomes were symptomatic recurrent VTE and major bleeding. Results: We analyzed 450 consecutive patients treated with rivaroxaban and referred them to the MAC Project database for unprovoked or recurrent VTE. Of these, 267 (55%) were unprovoked VTE, and 377 (87%) were symptomatic. We followed up with the patients for a mean of 22 months (Q1 10.7; Q3 37.4 months). Recurrent VTE occurred in 12 patients on rivaroxaban treatment (IR 1.7 per 100 person-years). Males had more recurrence than women. During the follow-up period, we recorded 13 (2.9%) major bleeding, 12 (2.7%) clinically relevant non-major bleeding, 8 minor bleeding, and no fatal bleeding events. Overall, bleeding events occurred in 33 (7.3%) patients, most occurring within the first 2 years of treatment. In addition, we observed a statistically significant higher incidence of bleeding in patients with a baseline HAS-BLED score of 3 to 4 compared with those with a score of 0 to 2, with most events occurring during the first 3 months of treatment (RR 5.9). Discussion: Rivaroxaban appears to be safe and effective for the long-term treatment of patients with recurrent or unprovoked VTE. Our results match previously published data, and we are confident that the continuation of the follow-up for up to 5 years will confirm these outcomes.

Complex Class 1 Integron in a Clinical Escherichia coli Strain From Vietnam Carrying Both mcr-1 and bla NDM-1.

The co-production of MCR and carbapenemase in Enterobacteriaceae has been previously reported. Here, we describe a clinical strain of Escherichia coli from Vietnam carrying both mcr-1 and bla NDM-1. Whole-genome sequencing showed that the genome of this strain consists of a 4,975,832-bp chromosome and four plasmids. The mcr-1 and bla NDM-1 genes are located on IncI2 and IncA/C2-type plasmids, respectively. Genetic analysis revealed the presence of a multidrug-resistant region with the structure of a novel complex class 1 integron including a class 1 integron region bearing two 5' conserved segments and one 3' conserved segment and two complete structures of ISCR1. The complex integron contains aminoglycoside resistance genes aadA2, aadB, strA, strB, and aphA6, quinolone resistance gene qnrA1, extended-spectrum ß-lactamase gene bla OXA- 4, and a Tn125-like transposon bearing bla NDM-1. In addition, the dfrA12-gcuF-aadA2-cmlA1-aadA1-qacH gene cassette array belonging to the sul3-type integron was also identified, but the region found downstream of the gene cassette array is the IS440-tet(M)-IS26 element instead of the sul3 gene. The results further support that Enterobacteriaceae isolates co-harboring mcr and bla NDM are widely being distributed. The structural characteristics of the complex integron reveal that ISCR1 elements play an important role in the mobilization of bla NDM-1 and the development of multidrug-resistant regions.

Characterization of a carbapenem- and colistin-resistant Enterobacter cloacae carrying Tn6901 in bla NDM-1 genomic context.

We report a clinical strain of Enterobacter cloacae, PIMB10EC27, isolated in Vietnam in 2010 that was resistant to 21 of 26 tested antibiotics, including carbapenems (MICs >64 µg/mL) and colistin (MIC >128 µg/mL). The complete genome of strain PIMB10EC27 was sequenced by PacBio RSII and the Illumina Miseq system. Whole-genome analysis revealed that PIMB10EC27 contains a chromosome of the ST513 group (PIMBEC27, length 5,272,177 bp) and two plasmids, pEC27-1 of the IncX3 group (length 62,470 bp) and pEC27-2 of the IncHI1 group (length 84,602 bp). It also revealed that strain PIMB10EC27 carries 15 genes that confer resistance to at least 10 antibiotic groups. Particularly, the insertion of ISKpn19 and Tn6901 into the genomic context of bla NDM-1 was first identified and described. In another context, amino acid mutations G273D in PmrB and F515S in PmrC were first identified on the chromosome of PIMB10EC27, which may confer resistance to colistin in this strain.

Coexistence Of Plasmid-Mediated mcr-1 And bla NDM-4 Genes In A Klebsiella pneumoniae Clinical Strain In Vietnam.

In this study, we characterized the first clinical Klebsiella pneumoniae strain co- harboring mcr-1 and bla NDM-4 genes in Vietnam, which was recovered from a patient admitted to hospital in 2015. This strain demonstrated nonsusceptible to all tested antibiotics, including last-line antibiotics such as carbapenems (MICs ≥128 µg/mL) and colistin (MIC =32 µg/mL), except tigecycline (MIC =1 µg/mL). Whole-genome analysis using both MinION and MiSeq data revealed that the strain carried 29 resistance genes. Particularly, mcr-1 and bla NDM-4 genes were carried by different self-conjugative plasmids and able to be transferred to a recipient by conjugation. The colistin resistance of this strain was conferred by mcr-1 and additional chromosomal resistance determinants. Eight amino acid substitutions found in PmrA, PmrB, PmrC, PmrI, and PmrJ, all proteins that are involved in lipopolysaccharide modifications, may be associated with chromosomal colistin resistance. The accumulation of multiple antibiotic resistance mechanisms in this clinical isolate raises alarm on potential spread of extensively drug-resistant K. pneumoniae in healthcare settings.