Progressive in vivo development of resistance to cefiderocol in Pseudomonas aeruginosa.

We report in vivo development of cefiderocol (FDC) resistance among four sequential Pseudomonas aeruginosa clinical isolates ST244 recovered from a single patient, without exposure to FDC, which raises concern about the effectiveness of this novel drug. The first recovered P. aeruginosa isolate (P-01) was susceptible to FDC (2 μg/mL), albeit this MIC value was higher than that of a wild-type P. aeruginosa (0.12-0.25 μg/ml). The subsequent isolated strains (P-02, P-03, P-04) displayed increasing levels of FDC MICs (8, 16, and 64 μg/ml, respectively). Those isolates also showed variable and gradual increasing levels of resistance to most β-lactams tested in this study. Surprisingly, no acquired β-lactamase was identified in any of those isolates. Whole-genome sequence analysis suggested that this resistance was driven by multifactorial mechanisms including mutational changes in iron transporter proteins associated with FDC uptake, ampC gene overproduction, and mexAB-oprM overexpression. These findings highlight that a susceptibility testing to FDC must be performed prior to any prescription

Antibiotic-related gut dysbiosis induces lung immunodepression and worsens lung infection in mice.

Gut dysbiosis due to the adverse effects of antibiotics affects outcomes of lung infection. Previous murine models relied on significant depletion of both gut and lung microbiota, rendering the analysis of immune gut-lung cross-talk difficult. Here, we study the effects of antibiotic-induced gut dysbiosis without lung dysbiosis on lung immunity and the consequences on acute P. aeruginosa lung infection. C57BL6 mice received 7 days oral vancomycin-colistin, followed by normal regimen or fecal microbial transplant or Fms-related tyrosine kinase 3 ligand (Flt3-Ligand) over 2 days, and then intra-nasal P. aeruginosa strain PAO1. Gut and lung microbiota were studied by next-generation sequencing, and lung infection outcomes were studied at 24 h. Effects of vancomycin-colistin on underlying immunity and bone marrow progenitors were studied in uninfected mice by flow cytometry in the lung, spleen, and bone marrow. Vancomycin-colistin administration induces widespread cellular immunosuppression in both the lung and spleen, decreases circulating hematopoietic cytokine Flt3-Ligand, and depresses dendritic cell bone marrow progenitors leading to worsening of P. aeruginosa lung infection outcomes (bacterial loads, lung injury, and survival). Reversal of these effects by fecal microbial transplant shows that these alterations are related to gut dysbiosis. Recombinant Flt3-Ligand reverses the effects of antibiotics on subsequent lung infection. These results show that gut dysbiosis strongly impairs monocyte/dendritic progenitors and lung immunity, worsening outcomes of P. aeruginosa lung infection. Treatment with a fecal microbial transplant or immune stimulation by Flt3-Ligand both restore lung cellular responses to and outcomes of P. aeruginosa following antibiotic-induced gut dysbiosis

First Observation of Parallax in a Gravitational Microlensing Event

We present the first detection of parallax effects in a gravitational microlensing event. Parallax in a gravitational microlensing event observed only from the Earth appears as a distortion of the lightcurve due to the motion of the Earth around the Sun. This distortion can be detected if the event duration is not much less than a year and if the projected velocity of the lens is not much larger than the orbital velocity of the Earth about the Sun. The event presented here has a duration of 220 days and clearly shows the distortion due to the Earth's motion. We find that the projected velocity of the lens is 75+/-5 km/s at an angle of 28+/-4 deg from the direction of increasing galactic longitude, as expected for a lens in the galactic disk. A likelihood analysis yields estimates of the distance to and mass of the lens: D_{lens} = 1.7 (+1.1/-0.7) kpc and M = 1.3 (+1.3/-0.6) Msun, suggesting that the lens is a remnant such as a white dwarf or neutron star. A less likely possibility is that the lens is a main sequence star. If so, we can add our upper limit on the observed flux from the lens to the analysis. This modifies the estimates to: D_{lens} = 2.8 (+1.1/-0.6) kpc, and M = 0.6 (+0.4/-0.2) Msun.Comment: 11 pages, 3 figs in uuencoded, compressed, tared postscript file