French national cohort of first use of dalbavancin: a high proportion of off-label use

Dalbavancin is a glycopeptide antibiotic with a long half-life, recently marketed in Europe for skin and soft tissue infections (SSTI), but real-life use is not well-known. We aimed to describe all first prescriptions in France over an 18-month period. We performed a retrospective study on all adult patients who received at least one dose of dalbavancin from July 1, 2017 to September 31, 2018. Data were collected thanks to a standard questionnaire. Failure was defined as: persistent or reappearance of signs of infection; and/or switch to suppressive antibiotic treatment; and/or death from infection. We included 75 patients from 29 French hospitals. Main indications were bone and joint infections (BJIs) (64.0%), endocarditis (25.3%), and SSTIs (17.3%). Main bacteria involved were: Staphylococcus aureus (51.4%), including methicillin-resistant S. aureus (MRSA) (19.4%); and coagulase-negative staphylococci (CNS) (44.4%). Median MICs for staphylococci to vancomycin and dalbavancin ranged from 0.875 mg/L to 2.0 mg/L, and 0.040 mg/L to 0.064 mg/L, respectively. Dalbavancin was used after a mean of 2.3 ± 1.2 lines of antimicrobial treatment. Main treatment regimens for dalbavancin were a weekly 2-dose regimen (1500mg each) in 38 (53.2%) cases, and a single-dose regimen (1500mg) in 13 (18.3%) cases. Overall, at the patients\u27 last visit, clinical cure was observed in 54/72 patients, while failure was found in 14/72 patients. First uses of dalbavancin in France were mostly off-label. Most of them were due to BJIs, and often as rescue therapy for severe infections. Even in off-label situations, dalbavancin seems safe and effective

Septic Shock Sera Containing Circulating Histones Induce Dendritic Cell–Regulated Necrosis in Fatal Septic Shock Patients

Objectives: Innate immune system alterations, including dendritic cell loss, have been reproducibly observed in patients with septic shock and correlated to adverse outcomes or nosocomial infections. The goal of this study is to better understand the mechanisms behind this observation in order to better assess septic shock pathogenesis.Design: Prospective, controlled experimental study. Setting: Research laboratory at an academic medical center. Subjects: The study enrolled 71 patients, 49 with septic shock and 22 with cardiogenic shock. Seventeen healthy controls served as reference. In vitro monocyte-derived dendritic cells were generated from healthy volunteers. Interventions: Sera were assessed for their ability to promote in vitro dendritic cell death through flow cytometry detection in each group of patients. The percentage of apoptotic or necrotic dendritic cells was evaluated by annexin-V and propidium iodide staining. Measurements and Main Results: We observed that only patients with septic shock and not patients with pure cardiogenic shock were characterized by a rapid and profound loss of circulating dendritic cells. In vitro analysis revealed that sera from patients with septic shock induced higher dendritic cell death compared to normal sera or cardiogenic shock (p < 0.005). Sera from surviving patients induced dendritic cell death through a caspase-dependent apoptotic pathway, whereas sera from nonsurviving patients induced dendritic cell-regulated necrosis. Dendritic cell necrosis was not due to necroptosis but was dependent of the presence of circulating histone. The toxicity of histones toward dendritic cell could be prevented by recombinant human activated protein C. Finally, we observed a direct correlation between the levels of circulating histones in patients and the ability of the sera to promote dendritic cell-regulated necrosis. Conclusions: The study demonstrates a differential mechanism of dendritic cell death in patients with septic shock that is dependent on the severity of the disease

Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection

BACKGROUND Clostridium difficile is the most common cause of infectious diarrhea in hospitalized patients. Recurrences are common after antibiotic therapy. Actoxumab and bezlotoxumab are human monoclonal antibodies against C. difficile toxins A and B, respectively. METHODS We conducted two double-blind, randomized, placebo-controlled, phase 3 trials, MODIFY I and MODIFY II, involving 2655 adults receiving oral standard-of-care antibiotics for primary or recurrent C. difficile infection. Participants received an infusion of bezlotoxumab (10 mg per kilogram of body weight), actoxumab plus bezlotoxumab (10 mg per kilogram each), or placebo; actoxumab alone (10 mg per kilogram) was given in MODIFY I but discontinued after a planned interim analysis. The primary end point was recurrent infection (new episode after initial clinical cure) within 12 weeks after infusion in the modified intention-to-treat population. RESULTS In both trials, the rate of recurrent C. difficile infection was significantly lower with bezlotoxumab alone than with placebo (MODIFY I: 17% [67 of 386] vs. 28% [109 of 395]; adjusted difference, −10.1 percentage points; 95% confidence interval [CI], −15.9 to −4.3; P<0.001; MODIFY II: 16% [62 of 395] vs. 26% [97 of 378]; adjusted difference, −9.9 percentage points; 95% CI, −15.5 to −4.3; P<0.001) and was significantly lower with actoxumab plus bezlotoxumab than with placebo (MODIFY I: 16% [61 of 383] vs. 28% [109 of 395]; adjusted difference, −11.6 percentage points; 95% CI, −17.4 to −5.9; P<0.001; MODIFY II: 15% [58 of 390] vs. 26% [97 of 378]; adjusted difference, −10.7 percentage points; 95% CI, −16.4 to −5.1; P<0.001). In prespecified subgroup analyses (combined data set), rates of recurrent infection were lower in both groups that received bezlotoxumab than in the placebo group in subpopulations at high risk for recurrent infection or for an adverse outcome. The rates of initial clinical cure were 80% with bezlotoxumab alone, 73% with actoxumab plus bezlotoxumab, and 80% with placebo; the rates of sustained cure (initial clinical cure without recurrent infection in 12 weeks) were 64%, 58%, and 54%, respectively. The rates of adverse events were similar among these groups; the most common events were diarrhea and nausea. CONCLUSIONS Among participants receiving antibiotic treatment for primary or recurrent C. difficile infection, bezlotoxumab was associated with a substantially lower rate of recurrent infection than placebo and had a safety profile similar to that of placebo. The addition of actoxumab did not improve efficacy. (Funded by Merck; MODIFY I and MODIFY II ClinicalTrials.gov numbers, NCT01241552 and NCT01513239.

The digestive system of rhynchoteuthion paralarvae (Cephalopoda: Ommastrephidae)

The anatomy of the digestive system and the digestive system enzymes of three types of rhynchoteuthion paralarvae A′, B′, and C′ (Illex) were studied. No differences among the three were found. The main features of the digestive system of these species of paralarval Ommastrephidae are described. The buccal mass is comprised of a beak and radula with conspicuous teeth. The well developed posterior salivary glands contain glandular tissue with two cell types: A, goblet cell, and B, granular cell. The esophagus is lined with a thin cuticle, but the stomach lacks cuticle and has a more strongly developed muscular wall than the esophagus. The large vestibule is lined with ciliated and glandular cells. Some primary folds of ciliated epithelial cells begin to develop in the caecum. The digestive gland is compact, round, red-pigmented and enclosed in a thick elastic capsule; it contains conspicuous inclusions: large boules, typical brown-body vacuoles and numerous lipid droplets. Thirteen hydrolases involved in digestive processes were examined. High proteasic activity and histochemically undetectable amylasic activity suggest a carnivorous diet. The occurrence of typical lysosomal enzymes in the digestive gland reveals a high intracellular digestive activity. The digestive system appeared to be developed and functional in the smallest specimens examined (ML: mantle length 1–2 mm). Typically juvenile features include the anterior part of the digestive system which is more highly developed than the posterior part, thus it is more functionally important than the posterior part. The muscular wall of the posterior part of the digestive tract is very thin: tractus with long cilia probably move food. Because the caecal leaflets are not yet fully developed, the digestive gland probably assumes the greatest part of the digestive and absorptive functions in paralarvae

Digestive Enzymes in Paralarval Cephalopods

Fourteen enzymes involved in digestion (esterases, glycosidases and peptidases) were localized by histochemical methods in planktonic paralarvae belonging to four families of cephalopods: Octopodidae, Bolitaenidae (Octopods), Ommastrephidae and Enoploteuthidae (Oegopsid squids). The high protease activity and very low or histochemically undetectable amylasic activity indicate a carnivorous diet suggesting that the diet of paralarvae resembles that of adults. The digestive gland displays the highest enzyme activities which agrees with the key role of the gland in the digestive processes of cephalopods. In particular, the gland appears to be the main source of the proteolytic enzymes found in the posterior digestive tract. The high acid phosphatase activity, DAP II and acetyl-glycosaminidase activities, typically lysosomal, point to intracellular digestive processes in the gland. The posterior salivary glands are as well developed in squids as in octopods and they display several enzyme activities, most notably a high proteolytic activity. This could indicate that the salivary glands would be more involved in the digestive processes in paralarval squids than in adults where they are mostly poison glands. In all of the specimens studied, the whole digestive system appears to be already developed and able to digest prey. The high level of alkaline phosphatase activity of the skin suggests active exchanges with the external medium. It seems possible therefore that nutrients could be absorbed through the skin and provide a part of the energy necessary to the young cephalopods

Evidence of 5-hydroxytryptamine synthesis in the follicles ofSepia officinalis and direct involvement in the control of egg-laying

International audienceAt the beginning of egg-laying, in the cuttlefish Sepia officinalis, the oocytes accumulated in the proximal oviduct are released into the mantle cavity by the contractions of the oviduct before being encapsulated and fertilised. A bioassay based on the recording of the contractile activity of the distal oviduct was performed to characterise the molecule(s) inhibiting the oviducal motility and then responsible for the storage of the oocytes before mating. From 200 full-grown oocytes, a factor lowering the oviducal contractions was purified and isolated by means of HPLC. ESI-MS as well as electrochemical detection following HPLC fractionation allowed identification of the 5-hydroxytryptamine in the pure fraction. The inhibition of the oviducal contractions by 5-HT was dose dependent with a threshold near 10(-7) M. An immunoenzymatic assay showed that 5-HT appeared in the follicles at the beginning of vitellogenesis and reached a maximum level in the full-grown oocytes. In vitro experiments revealed that 5-HT is synthesised by the follicular cells and the full-grown oocytes, before being released to target proximal oviduct. Thus 5-HT could be one of the molecules involved in the accumulation of oocytes in the oviduct before mating

Treatment of Prosthetic Vascular Graft Infections

International audienceProsthetic vascular graft infections require a medico-surgical treatment. A first-line, empirical, antimicrobial treatment could be administered in cases of severe sepsis, septic shock or mechanical complications such as aneurysm rupture or anastomotic leakage. A broad-spectrum combination (glycopeptide, beta-lactams, and aminoglycoside) is usually proposed. When bacteriological samples have identified the causal agent(s) and its antibiotics susceptibility, a treatment with a narrow spectrum will be prescribed during the 6 weeks following surgical treatment.When surgical treatment is suboptimal, a suppressive antibiotic therapy is administered lifelong. The surgical treatment for these patients is complex. It depends on the mechanism of infection, location of prosthetic graft, causal bacteria, and underlying diseases

Characterization of Streptococcus equi subsp. zooepidemicus isolates containing lnuB gene responsible for the L phenotype.

Within the framework of the β-hemolytic streptococci surveillance carried out by the National Reference Laboratory from Uruguay, three putative Streptococcus equi subsp. zooepidemicus (SEZ) were received from different health centers. Being these the first reports associated with human infections in Uruguay, the objective of this work was to confirm their identification, to determine their genetic relationship and to study their antibiotic susceptibility. Using four different methods, they were identified as SEZ, a subspecies which has been described as the etiologic agent of rare and severe zoonosis in a few cases in other countries. The three isolates presented different pulsotypes by PFGE; however, two of them appeared to be related and were confirmed as ST431 by MLST, while the remaining isolate displayed ST72. Their resistance profile exhibited an unexpected feature: despite all of them were susceptible to macrolides, they showed different levels of resistance to clindamycin, i.e. they had the so-called "L phenotype". This rare trait is known to be due to a nucleotidyl-transferase, encoded by genes of the lnu family. Although this phenotype was previously described in a few SEZ isolates, its genetic basis has not been studied yet. This was now analyzed by PCR in the three isolates and they were found to contain a lnuB gene. The lnuB sequence was identical among the three isolates and with many lnuB sequences deposited in data banks. In conclusion, for the first time in Uruguay, three SEZ isolates recovered from non-epidemiologically related cases of human invasive infection were identified. Moreover, this is the first report about the presence of a lnu gene in the S. equi species, revealing the active lateral spread of the lnuB in a new streptococcal host

Infective endocarditis caused by Streptococcus tigurinus-like organisms

Streptococcus species are important causes of infective endocarditis but species identification remains challenging. We report two cases of infective endocarditis due to Streptococcus tigurinus-like organisms, which were first identified by 16S ribosomal RNA gene sequence analysis and subsequently confirmed using phylogeny based on the analysis of the shetA gene encoding exfoliative toxin