Effect of Concomitant 3-Hydroxy-3-Methyl-Glutaryl-CoA Reductase Inhibitor Therapy on Creatine Phosphokinase Levels and Mortality Among Patients Receiving Daptomycin: Retrospective Cohort Study.

IntroductionThe prescribing information for daptomycin recommends discontinuing statin therapy during receipt of daptomycin. The literature supporting this recommendation is sparse. The objectives of this study were to examine the impact of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors (statins) on creatine phosphokinase (CPK) elevations and mortality among patients receiving daptomycin therapy.MethodsA retrospective cohort study was performed among daptomycin recipients in the Upstate New York Veterans' Healthcare Administration from September 15, 2003 to July 1, 2013. Inclusion criteria were: (1) daptomycin for ≥48 h, (2) availability of baseline CPK value and (3) >1 CPK level measurement taken while on therapy. The following were extracted from medical records: demographics, comorbidities, laboratory data, medication history (daptomycin, statins and concomitant drugs known to increase CPK), Acute Physiology and Chronic Health Evaluation (APACHE)-II score and vital status at 30 days. The exposure of interest was use of statins. The primary outcome was CPK elevation defined as a CPK value ≥3 times the upper limit of normal (ULN) if baseline CPK was normal, and ≥5 times ULN if baseline CPK was elevated. The secondary outcome was death within 30 days of commencing daptomycin.ResultsA total of 233 patients were included in this analysis. Among these patients, 53 received concomitant statin therapy. Most baseline clinical characteristics were similar between statin recipients and non-recipients. Five (2.1%) patients experienced a CPK elevation; 3/53 (5.7%) were statin recipients and 2/180 (1.1%) received daptomycin alone (p = 0.08). All patients with CPK elevations had normal baseline CPK values. No effect modification was observed by use of other concomitant medications known to increase CPK values. Death was observed more frequently among statin non-recipients (17.2%) than recipients (9.4%).ConclusionsAmong patients receiving daptomycin, no significant difference was observed in frequency of CPK elevation between statin recipients and non-recipients

Phylogenomics of the Reproductive Parasite Wolbachia pipientis wMel: A Streamlined Genome Overrun by Mobile Genetic Elements

The complete sequence of the 1,267,782 bp genome of Wolbachia pipientis wMel, an obligate intracellular bacteria of Drosophila melanogaster, has been determined. Wolbachia, which are found in a variety of invertebrate species, are of great interest due to their diverse interactions with different hosts, which range from many forms of reproductive parasitism to mutualistic symbioses. Analysis of the wMel genome, in particular phylogenomic comparisons with other intracellular bacteria, has revealed many insights into the biology and evolution of wMel and Wolbachia in general. For example, the wMel genome is unique among sequenced obligate intracellular species in both being highly streamlined and containing very high levels of repetitive DNA and mobile DNA elements. This observation, coupled with multiple evolutionary reconstructions, suggests that natural selection is somewhat inefficient in wMel, most likely owing to the occurrence of repeated population bottlenecks. Genome analysis predicts many metabolic differences with the closely related Rickettsia species, including the presence of intact glycolysis and purine synthesis, which may compensate for an inability to obtain ATP directly from its host, as Rickettsia can. Other discoveries include the apparent inability of wMel to synthesize lipopolysaccharide and the presence of the most genes encoding proteins with ankyrin repeat domains of any prokaryotic genome yet sequenced. Despite the ability of wMel to infect the germline of its host, we find no evidence for either recent lateral gene transfer between wMel and D. melanogaster or older transfers between Wolbachia and any host. Evolutionary analysis further supports the hypothesis that mitochondria share a common ancestor with the α-Proteobacteria, but shows little support for the grouping of mitochondria with species in the order Rickettsiales. With the availability of the complete genomes of both species and excellent genetic tools for the host, the wMel–D. melanogaster symbiosis is now an ideal system for studying the biology and evolution of Wolbachia infections

Effect of Concomitant 3-Hydroxy-3-Methyl-Glutaryl-CoA Reductase Inhibitor Therapy on Creatine Phosphokinase Levels and Mortality Among Patients Receiving Daptomycin: Retrospective Cohort Study.

IntroductionThe prescribing information for daptomycin recommends discontinuing statin therapy during receipt of daptomycin. The literature supporting this recommendation is sparse. The objectives of this study were to examine the impact of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors (statins) on creatine phosphokinase (CPK) elevations and mortality among patients receiving daptomycin therapy.MethodsA retrospective cohort study was performed among daptomycin recipients in the Upstate New York Veterans' Healthcare Administration from September 15, 2003 to July 1, 2013. Inclusion criteria were: (1) daptomycin for ≥48 h, (2) availability of baseline CPK value and (3) >1 CPK level measurement taken while on therapy. The following were extracted from medical records: demographics, comorbidities, laboratory data, medication history (daptomycin, statins and concomitant drugs known to increase CPK), Acute Physiology and Chronic Health Evaluation (APACHE)-II score and vital status at 30 days. The exposure of interest was use of statins. The primary outcome was CPK elevation defined as a CPK value ≥3 times the upper limit of normal (ULN) if baseline CPK was normal, and ≥5 times ULN if baseline CPK was elevated. The secondary outcome was death within 30 days of commencing daptomycin.ResultsA total of 233 patients were included in this analysis. Among these patients, 53 received concomitant statin therapy. Most baseline clinical characteristics were similar between statin recipients and non-recipients. Five (2.1%) patients experienced a CPK elevation; 3/53 (5.7%) were statin recipients and 2/180 (1.1%) received daptomycin alone (p = 0.08). All patients with CPK elevations had normal baseline CPK values. No effect modification was observed by use of other concomitant medications known to increase CPK values. Death was observed more frequently among statin non-recipients (17.2%) than recipients (9.4%).ConclusionsAmong patients receiving daptomycin, no significant difference was observed in frequency of CPK elevation between statin recipients and non-recipients

Genomic Organization and expression of Type IV Secretion Operons in <i>w</i>Mel

<p>(A) Organization of the nine <i>vir</i>-like CDSs (white arrows) and five adjacent CDSs that encode for either putative membrane-spanning proteins (black arrows) or non-<i>vir</i> CDSs (gray arrows) of wMel, R. conorii, and A. tumefaciens. Solid horizontal lines denote RT experiments that have confirmed that adjacent CDSs are expressed as part of a polycistronic transcript. Results of these RT-PCR experiments are presented in (B). Lane 1, <i>virB3</i>-<i>virB4</i>; lane 2, RT control; lane 3, <i>virB6</i>-WD0856; lane 4, RT control; lane 5, WD0856-WD0855; lane 6, RT control; lane 7, WD0854-WD0853; lane 8, RT control; lane 9, <i>virB8</i>-<i>virB9</i>; lane 10, RT control; lane 11, <i>virB9</i>-<i>virB11</i>; lane 12, RT control; lane 13, <i>virB11</i>-<i>virD4</i>; lane 14, RT control; lane 15, <i>virD4</i>-<i>wspB</i>; lane 16, RT control; lane 17, <i>virB4</i>-<i>virB6</i>; lane 18, RT control; lane 19, WD0855-WD0854; lane 20, RT control. Only PCRs that contain reverse transcriptase amplified the desired products. PCR primer sequences are listed in <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0020069#st009" target="_blank">Table S9</a>.</p

Phage Alignments and Neighboring Genes

<p>Conserved gene order between the WO phage in <i>Wolbachia</i> sp. <i>w</i>Kue and prophage regions of <i>w</i>Mel. Putative proteins in <i>w</i>Kue (<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0020069#pbio-0020069-Masui2" target="_blank">Masui et al. 2001</a>) were searched using TBLASTN against the <i>w</i>Mel genome. Matches with an <i>E</i>-value of less than 1e⁻¹⁵ are linked by connecting lines. CDSs are colored as follows: brown, phage structural or replication genes; light blue, conserved hypotheticals; red, hypotheticals; magenta, transposases or reverse transcriptases; blue, ankyrin repeat genes; light gray, <i>radC</i>; light green, paralogous genes; gold, others. The regions surrounding the phage are shown because they have some unusual features relative to the rest of the genome. For example, WO-A and WO-B are each flanked on one side by clusters of genes in two paralogous families that are distantly related to phage repressors. In each of these clusters, a homolog of the <i>radC</i> gene is found. A third <i>radC</i> homolog (WD1093) in the genome is also flanked by a member of one of these gene families (WD1095). While the connection between <i>radC</i> and the phage is unclear, the multiple copies of the <i>radC</i> gene and the members of these paralogous families may have contributed to the phage rearrangements described above.</p

Long Evolutionary Branches in <i>w</i>Mel

<p>Maximum-likelihood phylogenetic tree constructed on concatenated protein sequences of 285 orthologs shared among <i>w</i>Mel, R. prowazekii, R. conorii, <i>C. crescentus,</i> and E. coli. The location of the most recent common ancestor of the α-Proteobacteria (<i>Caulobacter</i>, <i>Rickettsia</i>, <i>Wolbachia</i>) is defined by the outgroup <i>E. coli.</i> The unit of branch length is the number of changes per amino acid. Overall, the amino acid substitution rate in the <i>w</i>Mel lineage is about 63% higher than that of <i>C. crescentus</i>, a free-living α-Proteobacteria. <i>w</i>Mel has evolved at a slightly higher rate than the <i>Rickettssia</i> spp., close relatives that are also obligate intracellular bacteria that have undergone accelerated evolution themselves. This higher rate is likely in part to be due to an increase in the rate of slightly deleterious mutations, although we have not ruled out the possibility of G+C content effects on the branch lengths.</p

Alignment of <i>w</i>Mel with a 60 kbp Region of the <i>Wolbachia</i> from <i>B. malayi</i>

<p>The figure shows BLASTN matches (green) and whole-proteome alignments (red) that were generated using the “promer” option of the MUMmer software (<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0020069#pbio-0020069-Delcher1" target="_blank">Delcher et al. 1999</a>). The B. malayi region is from a BAC clone (<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0020069#pbio-0020069-Ware1" target="_blank">Ware et al. 2002</a>). Note the regions of alignment broken up by many rearrangements and the presence of repetitive sequences at the regions of the breaks.</p

Circular Map of the Genome and Genome Features

<p>Circles correspond to the following: (1) forward strand genes; (2) reverse strand genes, (3) in red, genes with likely orthologs in both R. conorii and R. prowazekii; in blue, genes with likely orthologs in R. prowazekii, but absent from R. conorii; in green, genes with likely orthologs in R. conorii but absent from R. prowazekii; in yellow, genes without orthologs in either <i>Rickettsia</i> (<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0020069#st003" target="_blank">Table S3</a>); (4) plot is of χ² analysis of nucleotide composition; phage regions are in pink; (5) plot of GC skew (G–C)/(G+C); (6) repeats over 200 bp in length, colored by category; (7) in green, transfer RNAs; (8) in blue, ribosomal RNAs; in red, structural RNA.</p