Prospective role of cefiderocol in the management of carbapenem-resistant Acinetobacter baumannii infections: Review of the evidence

Carbapenem-resistant Acinetobacter baumannii (CRAB) has been classified by the World Health Organization as being in the critical category of pathogens requiring urgent new antibiotic treatment options. Cefiderocol, the first approved siderophore cephalosporin, was designed for the treatment of carbapenem-resistant Gram-negative pathogens, particularly the non-fermenting species A. baumannii and Pseudomonas aeruginosa. Cefiderocol is mostly stable against hydrolysis by serine β-lactamases and metallo-β-lactamases, which are leading causes of carbapenem resistance. This review collates the available evidence on the in vitro activity, pharmacokinetics/pharmacodynamics, and efficacy and safety of cefiderocol, and outlines its current role in the management of CRAB infections. In vitro surveillance data show susceptibility rates of \u3e90% for cefiderocol against CRAB isolates as well as in vitro synergism with a variety of antibiotics recommended in guidelines. Clinical efficacy of cefiderocol monotherapy against CRAB infections has been demonstrated in the descriptive, open-label CREDIBLE-CR and the non-inferiority, double-blind APEKS-NP randomised clinical trials as well as in real-world cases in patients with underlying health problems. To date, the frequency of on-therapy development of cefiderocol resistance in A. baumannii appears to be low, but monitoring is highly recommended. Within current treatment guidelines for moderate-to-severe CRAB infections, cefiderocol is recommended for infections in which other antibiotics failed and in combination with other active antibiotics. In vivo pre-clinical data support the combination of sulbactam or avibactam with cefiderocol to enhance efficacy and to suppress the emergence of cefiderocol resistance. The benefit of combination therapy in the clinical setting is yet to be determined in prospective studies

Strategies of initiation and streamlining of antibiotic therapy in 41 French intensive care units

CIAR (Club d'infectiologie en Anesthésie-Réanimation) Study Group: Pr B Allaouchiche (HCL, CHU Lyon), Pr C Arich (CHU Nimes), Pr C Auboyer (CHU St-Etienne), Dr JP Caramella (CHG Nevers), Dr JF Cochard (CHU Bordeaux), Dr A Combes (CHG Meaux), Dr P Courant (CHG Avignon), Dr J Durand-Gasselin (CHG Toulon), Pr J Duranteau (APHP, CHU Bicetre), Dr H Floch (CHU Nantes), Dr F Fraisse (CHG St Denis), Pr M Freysz (CHU Dijon), Dr B Garrigues (CHG Aix-en-Provence), Dr B Georges (CHU Toulouse), Pr F Gouin (APHM, CHU Marseille), Pr L Jacob (APHP, CHU St Louis), Pr P Juvin (APHP, CHU Beaujon), Dr J Keinlen (CHU Montpellier), Dr AM Korinek (APHP, CHU Pitie Salpetriere), Dr C Lamer (Institut Mutualiste Montsouris, Paris), Pr JY Lefrant (CHU Nimes), Dr O Lesieur (CHG La Rochelle), Dr Yazine Mahjoub (CHU Amiens), Pr Y Malledant (CHU Rennes), Pr C Martin (APHM, CHU Marseille), Pr O Mimoz (CHU Poitiers), Pr C Paugam-Burtz (APHP, CHU Beaujon, Clichy), Dr PF Perrigault (CHU Montpellier), Pr T Pottecher (CHU Strasbourg), Pr JL Pourriat (APHP, CHU Hotel Dieu), Dr JF Poussel (CHG Metz), Dr A Rabbat (APHP, CHU Hotel Dieu), Dr J Reignier (CHG La Roche sur Yon), Dr P Sichel (CHG Cherbourg), Dr JP Sollet (CHG Argenteuil), Dr D Thevenin (CHG Lens), Dr G Viquesnel (CHU Caen).International audienceINTRODUCTION: Few studies have addressed the decision-making process of antibiotic therapy (AT) in intensive care unit (ICU) patients. METHODS: In a prospective observational study, all consecutive patients admitted over a one-month period (2004) to 41 French surgical (n = 22) or medical/medico-surgical ICUs (n = 19) in 29 teaching university and 12 non-teaching hospitals were screened daily for AT until ICU discharge. We assessed the modalities of initiating AT, reasons for changes and factors associated with in ICU mortality including a specific analysis of a new AT administered on suspicion of a new infection. RESULTS: A total of 1,043 patients (61% of the cohort) received antibiotics during their ICU stay. Thirty percent (509) of them received new AT mostly for suspected diagnosis of pneumonia (47%), bacteremia (24%), or intra-abdominal (21%) infections. New AT was prescribed on day shifts (45%) and out-of-hours (55%), mainly by a single senior physician (78%) or by a team decision (17%). This new AT was mainly started at the time of suspicion of infection (71%) and on the results of Gram-stained direct examination (21%). Susceptibility testing was performed in 261 (51%) patients with a new AT. This new AT was judged inappropriate in 58 of these 261 (22%) patients. In ICUs with written protocols for empiric AT (n = 25), new AT prescribed before the availability of culture results (P = 0.003) and out-of-hours (P = 0.04) was more frequently observed than in ICUs without protocols but the appropriateness of AT was not different. In multivariate analysis, the predictive factors of mortality for patients with new AT were absence of protocols for empiric AT (adjusted odds ratio (OR) = 1.64, 95% confidence interval (95%CI): 1.01 to 2.69), age ≥60 (OR = 1.97, 95% CI: 1.19 to 3.26), SAPS II score >38 (OR = 2.78, 95% CI: 1.60 to 4.84), rapidly fatal underlying diseases (OR = 2.91, 95% CI: 1.52 to 5.56), SOFA score ≥6 (OR = 4.48, 95% CI: 2.46 to 8.18). CONCLUSIONS: More than 60% of patients received AT during their ICU stay. Half of them received new AT, frequently initiated out-of-hours. In ICUs with written protocols, empiric AT was initiated more rapidly at the time of suspicion of infection and out-of-hours. These results encourage the establishment of local recommendations for empiric AT

The Presence of Acinetobacter baumannii DNA on the Skin of Homeless People and Its Relationship With Body Lice Infestation. Preliminary Results

The presence of Acinetobacter baumannii was demonstrated in body lice, however, little is known about the mechanism of natural lice infection. In 2013 and 2014, cross-sectional one-day studies were therefore performed within two Marseille homeless shelters to assess the presence of A. baumannii DNA on human skin, blood and in body lice collected from the same homeless individuals. All 332 participants completed questionnaires, were examined for dermatologic signs, and provided four skin samples (hair, neck, armpits, and pelvic belt), blood samples and body lice (if any). We developed a new real-time PCR tool targeting the ompA/motB gene for the detection of A. baumannii for all collected samples. Blood culture was also performed. Body lice were found in 24/325 (7.4%) of subjects. We showed a prevalence of A. baumannii DNA skin-carriage in 33/305 (10.8%) of subjects. No difference was found in A. baumannii DNA prevalence according to body sites. A strong association between body lice infestation (OR = 3.07, p = 0.029) and A. baumannii DNA skin-carriage was noted. In lice, A. baumannii DNA was detected in 59/219 arthropods (26.9%). All blood cultures and real-time PCR on blood samples were negative for A. baumannii. Lice probably get infected with A. baumannii while biting through the colonized skin and likely transmit the bacteria in their feces. We found no evidence that lice facilitate the invasion of A. baumannii into the blood stream. Further investigations are needed to compare phenotypic and genotypic features of A. baumannii isolates from human skin and lice from the same individuals

Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV

The performance of muon reconstruction, identification, and triggering in CMS has been studied using 40 inverse picobarns of data collected in pp collisions at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection criteria covering a wide range of physics analysis needs have been examined. For all considered selections, the efficiency to reconstruct and identify a muon with a transverse momentum pT larger than a few GeV is above 95% over the whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4, while the probability to misidentify a hadron as a muon is well below 1%. The efficiency to trigger on single muons with pT above a few GeV is higher than 90% over the full eta range, and typically substantially better. The overall momentum scale is measured to a precision of 0.2% with muons from Z decays. The transverse momentum resolution varies from 1% to 6% depending on pseudorapidity for muons with pT below 100 GeV and, using cosmic rays, it is shown to be better than 10% in the central region up to pT = 1 TeV. Observed distributions of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO

Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV

The performance of muon reconstruction, identification, and triggering in CMS has been studied using 40 inverse picobarns of data collected in pp collisions at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection criteria covering a wide range of physics analysis needs have been examined. For all considered selections, the efficiency to reconstruct and identify a muon with a transverse momentum pT larger than a few GeV is above 95% over the whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4, while the probability to misidentify a hadron as a muon is well below 1%. The efficiency to trigger on single muons with pT above a few GeV is higher than 90% over the full eta range, and typically substantially better. The overall momentum scale is measured to a precision of 0.2% with muons from Z decays. The transverse momentum resolution varies from 1% to 6% depending on pseudorapidity for muons with pT below 100 GeV and, using cosmic rays, it is shown to be better than 10% in the central region up to pT = 1 TeV. Observed distributions of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO

Azimuthal anisotropy of charged particles at high transverse momenta in PbPb collisions at sqrt(s[NN]) = 2.76 TeV

The azimuthal anisotropy of charged particles in PbPb collisions at nucleon-nucleon center-of-mass energy of 2.76 TeV is measured with the CMS detector at the LHC over an extended transverse momentum (pt) range up to approximately 60 GeV. The data cover both the low-pt region associated with hydrodynamic flow phenomena and the high-pt region where the anisotropies may reflect the path-length dependence of parton energy loss in the created medium. The anisotropy parameter (v2) of the particles is extracted by correlating charged tracks with respect to the event-plane reconstructed by using the energy deposited in forward-angle calorimeters. For the six bins of collision centrality studied, spanning the range of 0-60% most-central events, the observed v2 values are found to first increase with pt, reaching a maximum around pt = 3 GeV, and then to gradually decrease to almost zero, with the decline persisting up to at least pt = 40 GeV over the full centrality range measured.Comment: Replaced with published version. Added journal reference and DO

Search for new physics with same-sign isolated dilepton events with jets and missing transverse energy

A search for new physics is performed in events with two same-sign isolated leptons, hadronic jets, and missing transverse energy in the final state. The analysis is based on a data sample corresponding to an integrated luminosity of 4.98 inverse femtobarns produced in pp collisions at a center-of-mass energy of 7 TeV collected by the CMS experiment at the LHC. This constitutes a factor of 140 increase in integrated luminosity over previously published results. The observed yields agree with the standard model predictions and thus no evidence for new physics is found. The observations are used to set upper limits on possible new physics contributions and to constrain supersymmetric models. To facilitate the interpretation of the data in a broader range of new physics scenarios, information on the event selection, detector response, and efficiencies is provided.Comment: Published in Physical Review Letter

Measurement of the Z/gamma* + b-jet cross section in pp collisions at 7 TeV

The production of b jets in association with a Z/gamma* boson is studied using proton-proton collisions delivered by the LHC at a centre-of-mass energy of 7 TeV and recorded by the CMS detector. The inclusive cross section for Z/gamma* + b-jet production is measured in a sample corresponding to an integrated luminosity of 2.2 inverse femtobarns. The Z/gamma* + b-jet cross section with Z/gamma* to ll (where ll = ee or mu mu) for events with the invariant mass 60 < M(ll) < 120 GeV, at least one b jet at the hadron level with pT > 25 GeV and abs(eta) < 2.1, and a separation between the leptons and the jets of Delta R > 0.5 is found to be 5.84 +/- 0.08 (stat.) +/- 0.72 (syst.) +(0.25)/-(0.55) (theory) pb. The kinematic properties of the events are also studied and found to be in agreement with the predictions made by the MadGraph event generator with the parton shower and the hadronisation performed by PYTHIA.Comment: Submitted to the Journal of High Energy Physic

Compressed representation of a partially defined integer function over multiple arguments

In OLAP (OnLine Analitical Processing) data are analysed in an n-dimensional cube. The cube may be represented as a partially defined function over n arguments. Considering that often the function is not defined everywhere, we ask: is there a known way of representing the function or the points in which it is defined, in a more compact manner than the trivial one

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns