Ortega, L. | Search bioRxiv

bioRxiv2018

Non-intravenous, carbapenem-sparing antibiotics for the treatment of bacteremia due to ESBL or AMP-C β-lactamase: A propensity score study

IntroductionCarbapenems are considered the treatment of choice for extended-spectrum {beta}-lactamase (ESBL) or Amp-C {beta}-lactamase-producing Enterobacteriaceae bacteremia. Data on the effectiveness of non-intravenous carbapenem-sparing antibiotic options are limited.\n\nObjectiveTo compare the 30 day-mortality and clinical failures associated with the use of carbapenems vs an alternative non-intravenous antibiotic for the definitive treatment of ESBL/Amp-C positive Enterobacteriaceae bacteremia.\n\nMethodsThis is a 12-year retrospective study (2004 - 2015) including all patients with bacteremia due to ESBL/Amp-C-producing Enterobacteriaceae. Given the lack of randomization of the initial therapies, a propensity score for receiving carbapenems was calculated.\n\nResultsThere were 1115 patients with a first episode of bacteremia due to E. coli or K. pneumoniae, of which 123 were ESBL/Amp C-positive (11%). There were 101 eligible patients: 59 in the carbapenem group and 42 in the alternative treatment group (cotrimoxazole 59.5%, quinolones 21.4%). The most frequent sources of infection were urinary (63%) and biliary (15%). Compared to the carbapenem group, patients treated with the alternative regimen had a shorter hospital stay (median [IQR]: 7 days [5-10] vs 12 days [9-18], p<0,001). The use of an alternative non-IV treatment did not increase mortality (OR 27; 95% CI 0.05-1.61; p=.15). After controlling for confounding factors with the propensity score, the adjusted OR of carbapenem treatment was 4.95; 95% CI (0.9426.01, p=.059).\n\nConclusionAlternative non-IV carbapenem-sparing antibiotics could have a role in the definitive treatment of ESBL/Amp-C-positive Enterobacteriaceae bloodstream infections, allowing a reduction in carbapenem use. The use of cotrimoxazole in this setting has shown favourable results.\n\nSome of the data contained in this article were presented at the 55th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) and at the 28th International Congress of Chemotherapy Meeting (ICC), San Diego, USA, 2015.

pathology↗

bioRxiv2018

QTL mapping of natural variation reveals that the developmental regulator bruno reduces tolerance to P-element transposition in the Drosophila female germline

Transposable elements (TEs) are obligate genetic parasites that propagate in host genomes by replicating in germline nuclei, thereby ensuring transmission to offspring. This selfish replication not only produces deleterious mutations---in extreme cases, TE mobilization induces genotoxic stress that prohibits the production of viable gametes. Host genomes could reduce these fitness effects in two ways: resistance and tolerance. Resistance to TE propagation is enacted by germline specific small-RNA-mediated silencing pathways, such as the piRNA pathway, and is studied extensively. However, it remains entirely unknown whether host genomes may also evolve tolerance, by desensitizing gametogenesis to the harmful effects of TEs. In part, the absence of research on tolerance reflects a lack of opportunity, as small-RNA-mediated silencing evolves rapidly after a new TE invades, thereby masking existing variation in tolerance.\n\nWe have exploited the recent the historical invasion of the Drosophila melanogaster genome by P-element DNA transposons in order to study tolerance of TE activity. In the absence of piRNA-mediated silencing, the genotoxic stress imposed by P-elements disrupts oogenesis, and in extreme cases leads to atrophied ovaries that completely lack germline cells. By performing QTL-mapping on a panel of recombinant inbred lines (RILs) that lack piRNA-mediated silencing of P- elements, we uncovered multiple QTL that are associated with differences in tolerance of oogenesis to P-element transposition. We localized the most significant QTL to a small 230 Kb euchromatic region, with the LOD peak occurring in the Bruno locus, which codes for a critical and well-studied developmental regulator of oogenesis. We further demonstrate that multiple bruno loss-of-function alleles are strong dominant suppressors of ovarian atrophy, allowing for the development of mature egg-chambers in the face of P-element activity. Genetic and cytological analyses suggest that bruno tolerance is explained by enhanced retention of germline stem cells in dysgenic ovaries, which are typically lost due to DNA damage. Our observations reveal segregating variation in TE tolerance for the first time, and implicate gametogenic regulators as a source of tolerant variants in natural populations.

genetics↗