High Risk Of Resistance Research Articles

Adaptation to Sodium Hypochlorite and Potassium Permanganate May Lead to Their Ineffectiveness Against Candida albicans.

Background/Objectives: Adaptation can reduce or completely eliminate the effectiveness of antibiotics and antiseptics at clinical concentrations. To our knowledge, no studies have examined fungal adaptation to antiseptics. This study aimed to preliminarily investigate the potential for Candida albicans adaptation to eight antiseptics. Methods: The minimal inhibitory concentration (MIC), drug susceptibility, adaptation to antiseptics, and Karpinski Adaptation Index (KAI) of C. albicans strains were assessed. Results: The antiseptics with the most effective MICs activity against C. albicans were octenidine dihydrochloride (OCT), chlorhexidine digluconate (CHX), and polyhexamethylene biguanide (polyhexanide, PHMB). Sodium hypochlorite (NaOCl) and ethacridine lactate (ET) demonstrated moderate activity, while boric acid (BA), povidone-iodine (PVI), and potassium permanganate (KMnO4) showed the weakest activity. The MIC values for NaOCl and KMnO4 were close to or equal to the clinical concentrations used in commercial products. The studied strains were susceptible to econazole, miconazole, and voriconazole. Resistance to other drugs occurred in 10-30% of the strains. Antifungal resistance remained unchanged after antiseptic adaptation testing. The lowest KAI values, indicating very low resistance risk, were observed for CHX, OCT, and PHMB. PVI and BA presented a low risk, ET a moderate risk. KMnO4 and NaOCl had the highest KAI values, indicating high and very high resistance risk in Candida yeasts. Conclusions:C. albicans strains can adapt to antiseptics to varying extents. For most antiseptics, adaptation does not significantly affect their clinical efficacy. However, due to adaptation, NaOCl and KMnO4 may become ineffective against C. albicans strains even at clinical concentrations.

Predicting monotherapy resistance risk in patients with low-risk gestational trophoblastic neoplasia: integration of the systemic immune-inflammation index and the prognostic nutritional index.

Currently, there are no reliable indicators for the early identification of patients with low-risk gestational trophoblastic neoplasia (GTN) who develop resistance to monotherapy. This study aimed to evaluate the effectiveness of combining the Systemic Immune-Inflammation Index (SII) and Prognostic Nutritional Index (PNI) in detecting early resistance to monotherapy in patients with low-risk GTN. This retrospective study included 91 patients with low-risk GTN who received initial monotherapy at Fujian Maternal and Child Health Hospital between 2013 and 2021. The SII and PNI before chemotherapy were calculated from prechemotherapy peripheral blood samples, with cut-off values determined by receiver operating characteristic (ROC) curves. The SII-PNI score ranged from 0 to 2 points and was categorized as follows: a score of 2 points indicated a high SII (≥467.02) and a low PNI (≤51.35); a score of 1 point indicated either a high SII or a low PNI; and a score of 0 points indicated neither a high SII nor a low PNI. Ninety-one patients with low-risk GTN underwent monotherapy, 19 of whom developed resistance, whereas the remaining 72 did not. The SII was significantly greater in chemotherapy-resistant patients than in non-resistant patients (P=0.04), whereas the PNI was markedly lower in chemotherapy-resistant patients (P=0.002). Univariate analysis revealed that cut-off values of 467.02 for the SII (P=0.04) and 51.35 for the PNI (P=0.024) were associated with chemotherapy resistance in patients with low-risk GTN. As the SII-PNI score increased, the proportion of chemotherapy-resistant patients increased (P<0.001), and the time for human chorionic gonadotropin (hCG) normalization correspondingly increased (P<0.001). Multivariate logistic regression analysis indicated that a high SII-PNI score is an independent risk factor for chemotherapy resistance in patients with low-risk GTN (P=0.001). A high SII and low PNI are linked to chemotherapy resistance in patients with low-risk GTN. The pretreatment SII-PNI score is a key indicator for predicting the sensitivity of patients with low-risk GTN to single-agent chemotherapy, aiding in the early identification of individuals at high risk of resistance.

Targeting MCL1-driven anti-apoptotic pathways overcomes blast progression after hypomethylating agent failure in chronic myelomonocytic leukemia

RAS pathway mutations, which are present in 30% of patients with chronic myelomonocytic leukemia (CMML) at diagnosis, confer a high risk of resistance to and progression after hypomethylating agent (HMA) therapy, the current standard of care for the disease. Here, using single-cell, multi-omics technologies, we seek to dissect the biological mechanisms underlying the initiation and progression of RAS pathway-mutated CMML. We identify that RAS pathway mutations induce transcriptional reprogramming of hematopoietic stem and progenitor cells (HSPCs) and downstream monocytic populations in response to cell-intrinsic and -extrinsic inflammatory signaling that also impair the functions of immune cells. HSPCs expand at disease progression after therapy with HMA or the BCL2 inhibitor venetoclax and rely on the NF-κB pathway effector MCL1 to maintain survival. Our study has implications for the development of therapies to improve the survival of patients with RAS pathway-mutated CMML.

High resistance risk of Phytophthora colocasiae to azoxystrobin in southeastern of China

Quinone outside inhibitor (QoI) has been applied to manage taro leaf blight caused by Phytophthora colocasiae in southeastern of China for many years. The risk of P. colocasiae to QoI and the potential resistant mechanism remain unknown. In this study, the 74 P. colocasiae strains were sampled from southeastern of China. Sequence analysis of the QoI target Cytb showed one nucleotide variant in the fragment of this gene in this population, producing two haplotypes. The nucleotide variant leads to codon change at 142 (GGT to GCT) producing A142 (alanine) and G142 (glycine) in Hap_1 and Hap_2 strains, respectively. The sensitivity differentiation to azoxystrobin of two haplotypes were observed in vitro. The Hap_1 and Hap_2 strains were confirmed resistant and sensitive by control efficacy of label rate fungicide application, which was 3.0% and 88.8% treated with 500 μg/mL azoxystrobin, respectively. In addition, 10.0 μg/mL azoxystrobin plus 50 μg/mL salicylhydroxamic acid (SHAM) supplemented in PDA medium was identified as a discriminatory dose for differentiation of these two phenotype strains. The azoxystrobin resistant frequency reached 86.5%, indicating prevalence of QoI resistance in the field. Further fitness related features showed that no significant difference in temperature sensitivity, mycelial growth rate, sporangia production, zoospore release and aggressiveness between azoxystrobin-resistant and sensitive strains indicating no potential fitness cost for azoxystrobin resistance. Taken together, azoxystrobin resistance need to be taken into consideration to manage taro leaf blight in southeastern of China.

The Phytochemistry profile of Piper betle extract and its Activity Against Hepatitis C Virus

Hepatitis C virus (HCV) is an RNA virus that is easy to mutate and high risk of resistance. The vaccine for HCV has not been provided yet, and the current treatment is very expensive. To provide alternative and complementary antiviral from plants, this study evaluated the activities of Piper betle (P. betle) against HCV and its combination with existing antiviral drugs, Ribavirin and Simeprevir. The antiviral inhibition was identified by in vitro culture using Huh7it-1 cells and JFH1a HCV. Moreover, the phytochemistry profile was also determined by Thin Layer Chromatography (TLC) and High-Performance Liquid Chromatography (HPLC). The result showed that the ethanol extract of P. betle was possess strong activity with an IC50 value of 0.08 ± 0.028 µg/mL. The mechanism of action revealed the extract dominantly inhibit in the post-entry steps. Furthermore, the combination of P. betle extract with simeprevir increased its anti-HCV activity, however, no effect was observed in the combination with ribavirin. The Western blotting analysis was shown inhibition of NS3 protein levels in a dose-dependent manner. Phytochemistry evaluation was shown for the extract containing flavonoids, polyphenols, and alkaloids. These results suggested that the ethanolic extract of P. betle could be a good candidate for the development or an alternative to anti-HCV drugs.&#x0D; Keywords: Hepatitis C Virus, Piper betle, Medicinal plants, Simeprevir, Ribavirin, Medicine.

Prediction of antibiotic sorption in soil with machine learning and analysis of global antibiotic resistance risk

Although the sorption of antibiotics in soil has been extensively studied, their spatial distribution patterns and sorption mechanisms still need to be clarified, which hinders the assessment of antibiotic resistance risk. In this study, machine learning was employed to develop the models for predicting the soil sorption behavior of three classes of antibiotics (sulfonamides, tetracyclines, and fluoroquinolones) in 255 soils with 2203 data points. The optimal independent models obtained an accurate predictive performance with R2 of 0.942 to 0.977 and RMSE of 0.051 to 0.210 on test sets compared to combined models. Besides, a global map of the antibiotic sorption capacity of soil predicted with the optimal models revealed that the sorption potential of fluoroquinolones was the highest, followed by tetracyclines and sulfonamides. Additionally, 14.3% of regions had higher antibiotic sorption potential, mainly in East and South Asia, Central Siberia, Western Europe, South America, and Central North America. Moreover, a risk index calculated with the antibiotic sorption capacity of soil and population density indicated that about 3.6% of soils worldwide have a high risk of resistance, especially in South and East Asia with high population densities. This work has significant implications for assessing the antibiotic contamination potential and resistance risk.

The link between farmers’ sowing date and herbicide management

This study presents an on-farm approach to investigate the impact of the sowing date on herbicide management in arable farming. Ten years of data (2012–2021) on the herbicide use and crop management practices of 4325 fields in north-eastern Germany were examined for winter barley, winter oilseed rape and winter wheat. We investigated whether the sowing date was related to the herbicide use intensity (described as Treatment Frequency Index, TFI) and mode of action (MoA) use (classified using the global HRAC classification).While the sowing of winter barley and winter oilseed rape took place over a short period of two weeks, sowing dates for winter wheat were spread over two months from the beginning of September to the end of October.Seventy-five percent of the winter barley fields were treated with HRAC group 2 herbicides and every second field was treated with herbicides in HRAC groups 15 and 3, respectively. Delayed autumn sowing of winter barley differing by 14 days decreased the in-crop use intensity of HRAC group 2 by up to 16%, for HRAC group 3 by up to 15% and for HRAC group 15 by up to 27%.In contrast, the herbicide management did not relate to the time of sowing in winter oilseed rape, except for HRAC groups 14 and 15.Ninety percent of the winter wheat fields were treated with HRAC group 2 herbicides and almost seventy-five percent with HRAC groups 15 herbicides, respectively. For winter wheat, our study provided evidence that delayed sowing dates in-mid October reduced the use intensity of HRAC group 2 by up to 41% and for HRAC 15 by up to 35%, respectively, compared with sowing at the beginning of September.With regard to the European-wide efforts to reduce chemical pesticide use by 50% by 2030, we conclude that cultural weed control with a sowing date delay may be highly effective at meeting this requirement. Additionally, delayed sowing dates have the potential to reduce the use intensity of MoA with a high resistance risk.

Predictive short/long-term efficacy biomarkers and resistance mechanisms of CD19-directed CAR-T immunotherapy in relapsed/refractory B-cell lymphomas.

Genetically modified T-cell immunotherapies are revolutionizing the therapeutic options for hematological malignancies, especially those of B-cell origin. Impressive efficacies of CD19-directed chimeric antigen receptor (CAR)-T therapy have been reported in refractory/relapsed (R/R) B-cell non-Hodgkin lymphoma (NHL) patients who were resistant to current standard therapies, with a complete remission (CR) rate of approximately 50%. At the same time, problems of resistance and relapse following CAR-T therapy have drawn growing attention. Recently, great efforts have been made to determine various factors that are connected to the responses and outcomes following CAR-T therapy, which may not only allow us to recognize those with a higher likelihood of responding and who could benefit most from the therapy but also identify those with a high risk of resistance and relapse and to whom further appropriate treatment should be administered following CAR-T therapy. Thus, we concentrate on the biomarkers that can predict responses and outcomes after CD19-directed CAR-T immunotherapy. Furthermore, the mechanisms that may lead to treatment failure are also discussed in this review.

Optimal Resistance Management for Mixtures of High-Risk Fungicides: Robustness to the Initial Frequency of Resistance and Pathogen Sexual Reproduction.

There is a strong consensus that selection for fungicide resistant pathogen strains can be most effectively limited by using applications of mixtures of fungicides designed to balance disease control against selection. However, how to do this in practice is not entirely characterized. Previous work indicates optimal mixtures of pairs of fungicides which are both at a high risk of resistance can be constructed using pairs of doses that select equally for both single resistant strains in the first year of application. What has not been addressed thus far is the important real-world case in which the initial levels of resistance to each fungicide differ, for example because the chemicals have been available for different lengths of time. We show how recommendations based on equal selection in the first year can be suboptimal in this case. We introduce a simple alternative approach, based on equalizing the frequencies of single resistant strains in the year that achieving acceptable levels of control is predicted to become impossible. We show that this strategy is robust to changes in parameters controlling pathogen epidemiology and fungicide efficacy. We develop our recommendation using a preexisting, parameterized model of Zymoseptoria tritici (the pathogen causing Septoria leaf blotch on wheat), which exemplifies the range of plant pathogens that predominantly spread clonally, but for which sexual reproduction forms an important component of the life cycle. We show that pathogen sexual reproduction can influence the rate at which fungicide resistance develops but does not qualitatively affect our optimal resistance management recommendation. [Formula: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY 4.0 International license.

440: ANTIMICROBIAL USE IN THE SECOND AND THIRD WAVE OF COVID-19 INFECTIONS IN A UK INTENSIVE CARE UNIT

Introduction: COVID-19 imposed a great amount of challenge and stress on global health care professionals. Critically ill patients were started on empirical antibiotics and antimicrobials at the beginning of the pandemic. However, studies have later shown that less than 10% of the patients with COVID-19 had a co-existing bacterial infection. Methods: The aim of this study was to calculate the prevalence of antimicrobial use on patients with COVID-19 in both waves two and three. The prime objective was to audit the use of antibiotics in patients with COVID-19 using the UK NICE guidelines and to observe the initial antimicrobials started for the patients in both waves. Information on patient demographic, antibiotics, laboratory results, and patient outcome were collected. Microsoft Excel Version 16.62 and IBM SPSS Statistics Version 28.0.1.1 (14) were used for statistical analysis. Results: In total 57.02% of patients from wave 2 had a confirmed infection. However, 80.2% of the wave 2 cohort were prescribed antibiotics. The antibiotics density for wave 2 averaged 0.92. 44.07% of the patients admitted during wave 3 had a laboratory-confirmed infection and 52.1% of the cohort were prescribed antibiotics. The average antibiotic density for wave three patients was 0.71. A higher proportion of this cohort had less cumulative days on antibiotics. 90 patients had 0-1 density in wave 3 compared to 84 in wave 2. Tazocin (Tazobactam and Pipercillin) was used the most in both cohort. It was used much more in wave 2 than wave 3. Tazocin is recommended by NICE as the first-line antimicrobial if the patient has severe symptoms, signs of sepsis, or is at higher risk of resistance. The second most common combination of initial antimicrobial was Amoxicillin and Clarithromycin. Conclusions: Physicians have become increasingly confident in diagnosing and managing patients with COVID-19 however, identification of a biomarker that can aid in distinguishing between viral and bacterial infections is necessary. During times of intense pressure and high demand, an objective marker, infection control liaison, and early microbiological input, helps minimise unnecessary antibiotic use.

Stellettin B Sensitizes Glioblastoma to DNA-Damaging Treatments by Suppressing PI3K-Mediated Homologous Recombination Repair.

Glioblastoma (GBM) is the most aggressive type of cancer. Its current first-line postsurgery regimens are radiotherapy and temozolomide (TMZ) chemotherapy, both of which are DNA damage-inducing therapies but show very limited efficacy and a high risk of resistance. There is an urgent need to develop novel agents to sensitize GBM to DNA-damaging treatments. Here it is found that the triterpene compound stellettin B (STELB) greatly enhances the sensitivity of GBM to ionizing radiation and TMZ in vitro and in vivo. Mechanistically, STELB inhibits the expression of homologous recombination repair (HR) factors BRCA1/2 and RAD51 by promoting the degradation of PI3Kα through the ubiquitin-proteasome pathway; and the induced HR deficiency then leads to augmented DNA damage and cell death. It is further demonstrated that STELB has the potential to rapidly penetrate the blood-brain barrier to exert anti-GBM effects in the brain, based on zebrafish and nude mouse orthotopic xenograft tumor models. The study provides strong evidence that STELB represents a promising drug candidate to improve GBM therapy in combination with DNA-damaging treatments.

Abstract 12339: Aggressive Additional Treatment Strategies to Eliminate Coronary Artery Aneurysms in Treatment-Resistant Kawasaki Disease

Introduction: Kawasaki disease (KD), which is the most common multisystem vasculitis with unknown causes in childhood, causes coronary artery aneurysms (CAAs) especially in treatment-resistant cases. Even with steroid combination therapy, sometimes the fever may persist or recur and requires several additional treatments, which cause CAAs. We reported previously about the scoring systems to predict non-responders to the initial steroid combination therapy. The aim of this study is to prove whether aggressive additional treatment strategies can prevent CAAs in patients at high risk of resistance to initial steroid combination therapy. Methods: The subjects were 39 KD patients with high scores in the scoring systems to predict non-responders to the initial steroid combination therapy*. *Patients who had high scores in all three predictive scoring systems in Japan, and scored 3 points or more in the following scoring system: Kobayashi scores ≥7, 2 points; Egami scores ≥4, 1 point; Number of neutrophils after initial treatment≥ 12000/μL, 2 points* Group 1 (n=26) received additional treatment after recurrent fever (ordinary strategy), Group 2 (n=13) received additional treatment before recurrent fever (aggressive strategy). We compared the incidence of CAAs (including transient dilatation) in each group. Results: In Group 1, there were 15 non-responders (58%) to the initial steroid combination therapy, compared to 0 in Group 2 (p&lt;0.01). All of them had recurrent fever after resolving the fever once. The median day of recurrent fever was day 6 [5.3-7]. In Group 1, there were 5 patients (19%) who had coronary artery dilation greater than z-score &gt;2.5 by treatment resistance, compared to 0 in Group 2 (p&lt;0.01). Conclusions: The aggressive additional treatment strategies (intervention before recurrent fever) prevent CAAs in patients at high risk of resistance to initial steroid combination therapy. Even if the fever is relieved once in the initial treatment, it seems important to prevent recurrent fever around day 7 when histological changes begin in high-risk patients.

Antifungal nanosuspensions with surfactants and silver for the treatment of onychomycosis

Fungal nail infection (Onychomycosis) often requires prolonged treatment and is associated with a high risk of resistance to treatment. Here in this contribution, we introduce a novel approach to enhance penetration and antifungal activity of the antifungal drug griseofulvin (GF). Solid dispersions were prepared with hydroxypropyl methylcellulose acetate succinate (HPMCAS) and combined with surfactant (either sodium dodecyl sulphate (SDS), dodecyl trimethylammonium bromide (DTAB), or Pluronic F127) using mechanochemical activation. The prepared powders were then suspended with spray-dried silica-coated silver nanoparticles and applied onto infected bovine hooves to assess permeability and antifungal activity. The results showed that the prepared nanosuspensions significantly suppressed fungal activity causing disruption of fungal biofilms. Raman mapping showed enhanced permeation while dynamic vapor sorption (DVS), and particle size measurements showed varied effects depending on the type of surfactant and milling conditions. The prepared nanosuspensions displayed enhanced solubility of the poorly soluble drug reaching approximately 1.2 mg/mL. The results showed that the dispersions that contained DTAB displayed maximum efficacy while the inclusion of colloidal silver did not seem to significantly improve the antifungal activity compared to other formulations.

The G143A/S substitution of mitochondrially encoded cytochrome b (Cytb) in Magnaporthe oryzae confers resistance to quinone outside inhibitors.

Rice blast, caused by Magnaporthe oryzae, is a destructive disease threatening the production of staple foods worldwide. Quinone outside inhibitors (QoIs) are a group of chemicals exhibiting excellent activity against a majority of plant pathogens, with the disadvantage that pathogens can easily develop resistance to QoIs. Here, we investigated the activity of picoxystrobin against M. oryzae, which showed a great inhibitory effect on 100 strains of M. oryzae with half-maximal effective concentrations (EC50 ) ranging from 0.0251 to 0.1337 μg ml-1 . The EC50 values showed a continuous unimodal distribution that was identical to the normal distribution, suggesting the potency of our study to represent baseline sensitivity. In addition, nine resistant mutants were obtained by exposing M. oryzae to a high dosage of picoxystrobin in the laboratory; all of them showed cross-resistance to the other five QoI fungicides. Although some mutants showed a decreased resistance factor after ten successive cultures on fungicide-free medium, the resistance to picoxystrobin was still inheritable. Amino acid substitution of G143S was detected in eight of nine picoxystrobin-resistant mutants, and G143A was detected in only one of nine mutants. A fitness penalty was found in the mutants carrying G143S rather than G143A. Our findings suggested that M. oryzae had a mid to high risk of resistance to picoxystrobin. Considering this, we should be vigilant to the resistance risk and apply picoxystrobin sensibly in the field. © 2022 Society of Chemical Industry.

Molecular Characterization and Antimicrobial Resistance of Pathogenic Escherichia coli Strains in Children from Wolaita Sodo, Southern Ethiopia.

Introduction Pathogenic Escherichia coli strains cause diarrheal infection in children due to their virulence factors. A nonanalytical observational study followed by a purposive sampling technique was conducted from October 2017 to June 2018, to determine the antimicrobial susceptibility patterns and molecularly detect pathogenic Escherichia coli strains in under-five children at Wolaita Sodo town using molecular and the Kirby-Bauer disc diffusion method. Result In the current investigation, out of 110 stool samples, Escherichia coli was isolated in 68 (61.8%) (95% CI: 52.1–70.9%). Out of 68 Escherichia coli isolates, 61.9% of Escherichia coli isolates were resistant, 9.4% were intermediately resistant, and 28.7% were susceptible. Among the antimicrobial agents, 91.2% of Escherichia coli isolates were highly sensitive to ciprofloxacin followed by norfloxacin (86.8%). Virulence genes were detected in 55.9% (38/68) (95% CI 52.1%–70.9%) of isolates. The following genes were detected: stx1 (6 (8.8%)), stx2 (4 (5.9%)), eaeA (5 (7.4%)), eaat (14 (20.5%)), and St (4 (5.9%)). Out of 68 Escherichia coli isolates, 43 (63.2%) isolates had shown multidrug resistance patterns. Furthermore, 11.8% of Escherichia coli isolates had shown resistance to eight different drugs. The multidrug resistance index value of Diarrheagenic Escherichia coli pathotypes was greater than or equal to 0.4, which indicates the high risk of resistance. Conclusion This study demonstrated important pathogenic Escherichia coli strains and multidrug resistance in isolates containing virulence genes. Wise use of antimicrobials and improving the hygienic practices amongst parents of children reduce its occurrence. Therefore, appropriate usage of antimicrobial agents should also be highly practiced in hospitals.

Functional characterization of MoSdhB in conferring resistance to pydiflumetofen in blast fungus Magnaporthe oryzae

AbstractBACKGROUNDRice (Oryza sativa) is an important cereal crop around the world, and has constantly been threaten by the most destructive fungus Magnaporthe oryzae. Pydiflumetofen, a novel succinate dehydrogenase inhibitor (SDHI), is currently being used for controlling various fungal diseases. However, the potential resistance risk of M. oryzae to pydiflumetofen has remained unclear to date, and finding the resistance mechanism is critical for the usage of this fungicide.RESULTSThe M. oryzae strain Guy11 is sensitive to pydiflumetofen, with EC50 value of 1.24 μg mL−1. 58 pydiflumetofen‐resistant (PR) mutants were obtained through pydiflumetofen‐induced spontaneous mutation, with a mean EC50 value &gt;500 μg mL −1, and the resistance factor (RF) &gt;400. The PR mutants displayed positive cross‐resistance to carboxin, but were more sensitive to fluopyram. Sequencing analysis showed that all PR mutants presented a cytosine‐to‐thymine transition at nucleotide position +1218, resulting in a replacement of histidine 245 by tyrosine (H245Y) on MoSdhB. The mutation of MoSdhB exhibited strong resistant phenotype, but no detectable growth deficits in fungal development, including vegetative growth and pathogenicity of M. oryzae. An allele‐specific PCR for rapid detection of the H245Y mutants was established in M. oryzae.CONCLUSIONThe M. oryzae is sensitive to pydiflumetofen, and shows a medium to high resistance risk to pydiflumetofen. A point mutation of MoSdhB (H245Y) is responsible for the fungal resistance to pydiflumetofen in M. oryzae. © 2022 Society of Chemical Industry.

Analysis of resistance risk and resistance-related point mutations in Cyt b of QioI fungicide ametoctradin in Phytophthora litchii.

Litchi downy blight, caused by Phytophthora litchii, is one of the most important diseases of litchi. Ametoctradin, as the only QioI (quinone inside and outside inhibitor) fungicide, has been registered in China in 2019. However, the ametoctradin-resistance risk and molecular basis in Phytophthora litchii have not been reported. In this study, the sensitivity profile of 144 Phytophthora litchii strains to ametoctradin was determined, with a mean median effective concentration (EC50 ) value of 0.1706 ± 0.091 μg mL-1 . Nine stable resistant Phytophthora litchii mutants [resistance factor (RF) > 400] were derived from sensitive isolates using fungicide adaption. The compound fitness index of three resistant-mutants (HN10-1-1, HN10-1-2 and HN10-2-1) was similar or higher than that of their parental isolates in vitro. All these ametoctradin-resistant mutants were sensitive to metalaxyl, dimethomorph, oxathiapiprolin and cyazofamid. Two point mutations, leading to the S33L and D228N changes in PlCyt b (cytochrome b) were found in ametoctradin-resistant mutants. Eight ametoctradin-resistant mutants containing S33L showed increased sensitivity to azoxystrobin and amisulbrom, and one mutant containing D228N exhibited increased sensitivity to cyazofamid. In vitro enzyme activity test showed that ametoctradin could not inhibit the activity of cytochrome bc1 complex with S33L and D228N point mutation. AS-PCR primers were designed based on the S33L change to detect the ametoctradin-resistant strains in the future. These results suggest that Phytophthora litchii has a medium to high resistance risk to ametoctradin in the laboratory. Two changes, S33L and D228N, in PlCyt b are likely to be associated with the observed ametoctradin resistance. © 2022 Society of Chemical Industry.

Empiric antimicrobial therapy for early-onset pneumonia in severe trauma patients.

The bacterial ecology involved in early pneumonia of severetrauma patients is mostly commensal and would allow wide use of narrow-spectrum antibiotics. We describe risk factors for treatment failure of severe trauma patients' pneumonia with the use of narrow-spectrum antimicrobial therapy in orderto develop a score that could help clinicians to determine which patients might be treated with narrow-spectrum antibiotics. A retrospective, observational, monocentric cohort study was conducted of severe trauma patients requiring mechanical ventilation for > 48h and developing a first episode of microbiologically confirmed pneumonia occurring within the first 10 days after admission. Overall, 370 patients were included. The resistance rate against narrow-spectrum antibiotics (amoxicillin/clavulanic acid) was 22.7% (84 pneumonia). In a multivariate analysis, two independent risk factors were associated with this resistance: prior antimicrobial therapy ≥ 48h (OR 4.00; 95 CI [2.39; 6.75]) and age ≥ 30y (OR 2.10; 95 CI [1.21; 3.78]). We created a prediction score that defined patient with one or two risk factors at high risk of resistance. This score presented a sensitivity of 0.92 [0.88; 0.94], a specificity of 0.33 [0.28; 0.38], a positive predictive value of 0.29 [0.24; 0.33] and a negative predictive value of 0.93 [0.90; 0.95]. Simple risk factors may help clinicians to identify severe trauma patients at high risk of pneumonia treatment failure with the use of narrow-spectrum antimicrobial therapy and, thus, use better tailored empiric therapy and limit the use of unnecessary broad-spectrum antimicrobial therapy.

The Effect in Renal Function and Vascular Decongestion in Type 1 Cardiorenal Syndrome Treated with Two Strategies of Diuretics, a Pilot Randomized Trial

AimThe main treatment strategy in type 1 cardiorenal syndrome (CRS1) is vascular decongestion. It is probable that sequential blockage of the renal tubule with combined diuretics (CD) will obtain similar benefits compared with stepped-dose furosemide (SF).MethodsIn a pilot double-blind randomized controlled trial of CRS1 patients were allocated in a 1:1 fashion to SF or CD. The SF group received a continuous infusion of furosemide 100 mg during the first day, with daily incremental doses to 200 mg, 300 mg and 400 mg. The CD group received a combination of diuretics, including 4 consecutive days of oral chlorthalidone 50 mg, spironolactone 50 mg and infusion of furosemide 100 mg. The objectives were to assess renal function recovery and variables associated with vascular decongestion.ResultsFrom July 2017 to February 2020, 80 patients were randomized, 40 to the SF and 40 to the CD group. Groups were similar at baseline and had several very high-risk features. Their mean age was 59 ± 14.5 years, there were 37 men (46.2%). The primary endpoint occurred in 20% of the SF group and 15.2% of the DC group (p = 0.49). All secondary and exploratory endpoints were similar between groups. Adverse events occurred frequently (85%) with no differences between groups (p = 0.53).ConclusionIn patients with CRS1 and a high risk of resistance to diuretics, the use of CD compared to SF offers the same results in renal recovery, diuresis, vascular decongestion and adverse events, and it can be considered an alternative treatment. ClinicalTrials.gov with number NCT04393493 on 19/05/2020 retrospectively registered.

Impact of Generic Entry on Hospital Antimicrobial Use: A Retrospective Quasi-Experimental Interrupted Time Series Analysis

Background: The impact of antimicrobials generic entry (GE) is controversial. Their introduction could provide an economic benefit yet may also increase their consumption, leading to a higher risk of resistance. Our aim was to analyze the impact of GE on trends of antimicrobial consumption in an acute-care hospital. Methods: A retrospective quasi-experimental interrupted time series analysis was conducted at a 400-bed tertiary hospital in Barcelona, Spain. All antimicrobials for systemic use for which a generic product entered the hospital from January 2000 to December 2019 were included. Antimicrobial consumption was expressed as DDD/100 bed days. Results: After GE, the consumption of cefotaxime (0.09, p < 0.001), meropenem (0.54, p < 0.001), and piperacillin-tazobactam (0.13, p < 0.001) increased, whereas the use of clindamycin (−0.03, p < 0.001) and itraconazole (−0.02, p = 0.01) was reduced. An alarming rise in cefepime (0.004), daptomycin (1.02), and cloxacillin (0.05) prescriptions was observed, despite not achieving statistical significance. On the contrary, the use of amoxicillin (−0.07), ampicillin (−0.02), cefixime (−0.06), fluconazole (−0.13), imipenem–cilastatin (−0.50) and levofloxacin (−0.35) decreased. These effects were noticed beyond the first year post GE. Conclusions: GE led to an increase in the consumption of broad-spectrum molecules. The potential economic benefit of generic antibiotics could be diluted by an increase in resistance. Antimicrobial stewardship should continue to monitor these molecules despite GE.