Summary Background The best available treatment against carbapenemase-producing Enterobacteriaceae (CPE) is unknown. The objective of this study was to investigate the effect of appropriate therapy ...and of appropriate combination therapy on mortality of patients with bloodstream infections (BSIs) due to CPE. Methods In this retrospective cohort study, we included patients with clinically significant monomicrobial BSIs due to CPE from the INCREMENT cohort, recruited from 26 tertiary hospitals in ten countries. Exclusion criteria were missing key data, death sooner than 24 h after the index date, therapy with an active antibiotic for at least 2 days when blood cultures were taken, and subsequent episodes in the same patient. We compared 30 day all-cause mortality between patients receiving appropriate (including an active drug against the blood isolate and started in the first 5 days after infection) or inappropriate therapy, and for patients receiving appropriate therapy, between those receiving active monotherapy (only one active drug) or combination therapy (more than one). We used a propensity score for receiving combination therapy and a validated mortality score (INCREMENT-CPE mortality score) to control for confounders in Cox regression analyses. We stratified analyses of combination therapy according to INCREMENT-CPE mortality score (0–7 low mortality score vs 8–15 high mortality score). INCREMENT is registered with ClinicalTrials.gov , number NCT01764490. Findings Between Jan 1, 2004, and Dec 31, 2013, 480 patients with BSIs due to CPE were enrolled in the INCREMENT cohort, of whom we included 437 (91%) in this study. 343 (78%) patients received appropriate therapy compared with 94 (22%) who received inappropriate therapy. The most frequent organism was Klebsiella pneumoniae (375 86% of 437; 291 85% of 343 patients receiving appropriate therapy vs 84 89% of 94 receiving inappropriate therapy) and the most frequent carbapenemase was K pneumoniae carbapenemase (329 75%; 253 74% vs 76 81%). Appropriate therapy was associated with lower mortality than was inappropriate therapy (132 38·5% of 343 patients died vs 57 60·6% of 94; absolute difference 22·1% 95% CI 11·0–33·3; adjusted hazard ratio HR 0·45 95% CI 0·33–0·62; p<0·0001). Among those receiving appropriate therapy, 135 (39%) received combination therapy and 208 (61%) received monotherapy. Overall mortality was not different between those receiving combination therapy or monotherapy (47 35% of 135 vs 85 41% of 208; adjusted HR 1·63 95% CI 0·67–3·91; p=0·28). However, combination therapy was associated with lower mortality than was monotherapy in the high-mortality-score stratum (30 48% of 63 vs 64 62% of 103; adjusted HR 0·56 0·34–0·91; p=0·02), but not in the low-mortality-score stratum (17 24% of 72 vs 21 20% of 105; adjusted odds ratio 1·21 0·56–2·56; p=0·62). Interpretation Appropriate therapy was associated with a protective effect on mortality among patients with BSIs due to CPE. Combination therapy was associated with improved survival only in patients with a high mortality score. Patients with BSIs due to CPE should receive active therapy as soon as they are diagnosed, and monotherapy should be considered for those in the low-mortality-score stratum. Funding Spanish Network for Research in Infectious Diseases, European Development Regional Fund, Instituto de Salud Carlos III, and Innovative Medicines Initiative.
The occurrence of multiple herbicide resistant weeds has increased considerably in glyphosate-resistant soybean fields in Brazil; however, the mechanisms governing this resistance have not been ...studied. In its study, the target-site and nontarget-site mechanisms were characterized in an Eleusine indica population (R-15) with multiple resistance to the acetyl-CoA carboxylase (ACCase) inhibitors, glyphosate, imazamox, and paraquat. Absorption and translocation rates of 14C-diclofop-methyl14C-imazamox and 14C-glyphosate of the R-15 population were similar to those of a susceptible (S-15) population; however, the R-15 population translocated ∼38% less 14C-paraquat to the rest of plant and roots than the S-15 population. Furthermore, the R-15 plants metabolized (by P450 cytochrome) 55% and 88% more diclofop-methyl (conjugate) and imazamox (imazamox–OH and conjugate), respectively, than the S-15 plants. In addition, the Pro-106-Ser mutation was found in the EPSPS gene of this population. This report describes the first characterization of the resistance mechanisms in a multiple herbicide resistant weed from Brazil.
This text assumes and departs from three basic premises: 1) identities are not born but constructed through repeated performative actions that are in turn informed by existing social constructions of ...gender; 2) analysing and understanding the ways in which gender is shared and historically constructed can lead to a construction of gender that goes beyond the binary system on which heteronormativity depends; 3) feminism is inherently democratic and entails the consolidation of the very conception of democracy. If feminism wants to remain so, it concludes, it cannot but embrace the theoretical framework and action of non-binary citizenship conceived by Queer Theory.
Acetolactate synthase (ALS) inhibiting herbicides (group 2) have been widely applied for the last 20 years to control
Sinapis alba
in cereal crops from southern Spain. In 2008, a tribenuron-methyl ...(TM) resistant (R)
S. alba
population was first reported in a cereal field in Malaga (southern Spain). In 2018, three suspected R
S. alba
populations (R1, R2 and R3) to TM were collected from three different fields in Granada (southern Spain, 100 km away from Malaga). The present work aims to confirm the putative resistance of these populations to TM and explore their resistance mechanisms. Dose–response assays showed that the R1, R2 and R3 populations ranging between 57.4, 44.4 and 57.1 times more resistance to TM than the susceptible population (S). A mutation in the
ALS
gene (Asp376Glu) was detected in the Rs
S. alba
populations.
14
C-metabolism studies show that metabolites and TM were changing significantly faster in the R than in the S plants. Alternative chemical control trials showed that 2,4-D and MCPA (auxin mimics), glyphosate (enolpyruvyl shikimate phosphate synthase,EPSPS, inhibitor-group 9), metribuzin (PSII inhibitors/Serine 264 Binders, -group 5) and mesotrione (hydroxyphenyl pyruvate dioxygenase, HPPD, inhibitor-group 27) presented a high control of the four populations of
S. alba
tested, both S and R. Based on these results, it is the first case described where the Asp376Glu mutation and P450-mediated metabolism participates in resistance to TM in
S. alba
. Comparing these results with those found in the
S. alba
population in Malaga in 2008, where the resistance was TSR type (Pro197Ser), we can suggest that despite the geographical proximity (over 100 km), the resistance in these cases was due to different evolutionary events.
Multiple resistance mechanisms to ALS inhibitors and auxin mimics in two Papaver rhoeas populations were investigated in wheat fields from Portugal. Dose-response trials, also with malathion (a ...cytochrome P450 inhibitor), cross-resistance patterns for ALS inhibitors and auxin mimics, alternative herbicides tests, 2,4-D and tribenuron-methyl absorption, translocation and metabolism experiments, together with ALS activity, gene sequencing and enzyme modelling and ligand docking were carried out. Results revealed two different resistant profiles: one population (R1) multiple resistant to tribenuron-methyl and 2,4-D, the second (R2) only resistant to 2,4-D. In R1, several target-site mutations in Pro197 and enhanced metabolism (cytochrome P450-mediated) were responsible of tribenuron-methyl resistance. For 2,4-D, reduced transport was observed in both populations, while cytochrome P450-mediated metabolism was also present in R1 population. Moreover, this is the first P. rhoeas population with enhanced tribenuron-methyl metabolism. This study reports the first case for P. rhoeas of the amino acid substitution Pro197Phe due to a double nucleotide change. This double mutation could cause reduced enzyme sensitivity to most ALS inhibitors according to protein modelling and ligand docking. In addition, this study reports a P. rhoeas population resistant to 2,4-D, apparently, with reduced transport as the sole resistance mechanism.
Display omitted
•Tribenuron P450-mediated metabolism is first reported in Papaver rhoeas.•The double mutation Pro197Phe is found for the first time in P. rhoeas, second world case.•Ligand docking predicts cross resistance to ALS inhibitors for the Pro197Phe.•Impaired transport alone could confer cross-resistance to all auxin mimics.•Various resistance mechanisms evolve in P. rhoeas to ALS inhibitors and auxin mimics.
The levels of resistance to glyphosate of 13 barnyard grass (
) populations harvested across different agriculture areas in the Southern Iberian Peninsula were determined in greenhouse and laboratory ...experiments. Shikimate accumulation fast screening separated the populations regarding resistance to glyphosate: susceptible (S) E2, E3, E4, and E6 and resistant (R) E1, E5, E7, E8, E9, E10, E11, E12, and E13. However, resistance factor (GR
E1-E13/GR
E6) values separated these populations into three groups: (S) E2, E3, E4, and E6, (R) E1, E5, E7, E8, and E9, and very resistant (VR) E10, E11, E12, and E13.
C-glyphosate assays performed on two S populations (E2 and E6) showed greater absorption and translocation than those found for R (E7 and E9) and VR (E10 and E12) populations. No previous population metabolized glyphosate to amino methyl phosphonic acid (AMPA) and glyoxylate, except for the E10 population that metabolized 51% to non-toxic products. The VR populations showed two times more 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) activity without herbicide than the rest, while the inhibition of the EPSPS activity by 50% (I
) required much higher glyphosate in R and VR populations than in S populations. These results indicated that different target-site and non-target-site resistance mechanisms were implicated in the resistance to glyphosate in
. Our results conclude that resistance is independent of climate, type of crop, and geographic region and that the level of glyphosate resistance was mainly due to the selection pressure made by the herbicide on the different populations of
studied.
At present, appearance of herbicide resistant weeds is not new because repeated herbicide treatments per agricultural year/cycle are usual in both perennial and annual crops worldwide. Characterizing ...resistance mechanisms implied in each herbicide resistant weed is the best tool and the basis to develop integrated weed management (IWM) strategies. The main resistance mechanisms which confer low sensibility to glyphosate in a previously confirmed glyphosate-resistant Chloris radiata population (ChrR), occurring in Colombian rice fields, were characterized. Pure line selection by clone plants showed high resistance levels in ChrR. Comparing with GR50 and LD50 values, ChrR was 9.6 and 10.8 times more resistant with respect to a representative susceptible population (ChrS). The nontarget site mechanisms reduced glyphosate absorption and translocation did not contribute to the glyphosate resistance of the ChrR population. However, enzyme activity assays and DNA sequencing demonstrated that at least one target-site resistance mechanism is involved in such resistance. All ten ChrR plants tested had the amino acid substitution Pro-106-Ser. The results may be crucial to decrease the resistance distribution of C. radiata in Colombia by implementing IWM programs. The change in weed control strategies in rice fields from Colombia must include herbicides with different mode of action from glyphosate and non chemical methods to preserve the useful life of glyphosate longer for weed control in the country.
•TSR and NTSR mechanisms involved in the glyphosate resistance of C. radiata were characterized.•Reduced 14C-glyphosate absorption and translocation did not contribute to glyphosate resistance.•One single mutation (Pro-106-Ser) was found in the gene encoding EPSPS of resistant plants.•This is the first characterization of the herbicide resistance mechanisms in a weed from Colombia.
Centaurea is a genus of winter weeds with a similar life cycle and competitive traits, which occurs in small-grains production fields in the central-southern of the Iberian Peninsula. However, most ...of herbicides recommended for weed management in wheat show poor control of Centaurea species. This study summarizes the biology, herbicide tolerance to acetolactate synthase (ALS) inhibitors, and recommended chemical alternatives for the control of Centaurea species. Four species (C. cyanus L., C. diluta Aiton, C. melitensis L. and C. pullata L. subsp. baetica Talavera), taxonomically characterized, were found as the main important broadleaf weeds in small-grains production fields of the Iberian Peninsula. These species showed innate tolerance to tribenuron-methyl (TM), showing LD50 values (mortality of 50% of a population) higher than the field dose of TM (20 g ai ha−1). The order of tolerance was C. diluta (LD50 = 702 g ha−1) ≫ C. pullata (LD50 = 180 g ha−1) ≫ C. cyanus (LD50 = 65 g ha−1) > C. melitensis (LD50 = 32 g ha−1). Centaurea cyanus and C. melitensis presented higher foliar retention (150–180 μL herbicide solution), absorption (14–28%) and subsequent translocation (7–12%) of TM with respect to the other two species. Centaurea spp. plants were able to metabolize 14C-TM into non-toxic forms (hydroxylated OH-metsulfuron-methyl and conjugated-metsulfuron-methyl), with cytochrome P450 (Cyt-P450) monooxygenases being responsible for herbicide detoxification. Centaurea cyanus and C. mellitensis metabolized up to 25% of TM, while C. diluta and C. pullata metabolized more than 50% of the herbicide. Centaurea species showed 80–100% survival when treated with of florasulam, imazamox and/or metsulfuron-methyl, i.e., these weeds present cross-tolerance to ALS inhibitors. In contrast, auxin mimics herbicides (2,4-D, clopyralid, dicamba, fluroxypir and MCPA) efficiently controlled the four Centaurea species. In addition, the mixture of ALS-inhibitors and auxin mimics also proved to be an interesting alternative for the control of Centaurea. These results show that plants of the genus Centaurea found in the winter cereal fields of the Iberian Peninsula have an innate tolerance to TM and cross-resistance to other ALS-inhibiting herbicides, governed by reduced absorption and translocation, but mainly by the metabolization of the herbicide via Cyt-P450.
Display omitted
•Four Centaurea sp. shown low susceptibility to tribenuron-methyl (TM).•CYP450 inhibitors antagonize tolerance to TM.•GST inhibitor do not antagonize the tolerance to TM.•Absorption and translocation differences were found in the four Centaurea.•Auxin mimics, alone or in mixture with other herbicides can be alternatives.
PDF
