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BMC Microbiology Mar 2024The intrinsic concentration of RpoS, the second most abundant sigma factor, varies widely across the E. coli species. Bacterial isolates that express high levels of RpoS...
BACKGROUND
The intrinsic concentration of RpoS, the second most abundant sigma factor, varies widely across the E. coli species. Bacterial isolates that express high levels of RpoS display high resistance to environmental stresses, such as temperature, pH and osmolarity shifts, but are less nutritional competent, making them less capable of utilising alternative nutrient sources. The role of RpoS in antibiotic resistance and persistence in standard laboratory domesticated strains has been examined in several studies, most demonstrating a positive role for RpoS.
RESULTS
Using disk diffusion assays we examined bacterial resistance to 15 different antibiotics, including -lactams (penicillins, monobactams, carbapenems and cephalosporins), aminoglycosides, quinolones and anti-folates, in a representative collection of 328 E. coli natural isolates displaying a continuum of different levels of RpoS. There was an overall trend that isolates with higher levels of RpoS were slightly more resistant to these antibiotics. In addition, the effect of RpoS on bacterial tolerance and persistence to 3 different antibiotics - ampicillin, ciprofloxacin and kanamycin was evaluated through time-kill curves. Again, there was a small beneficial effect of RpoS on tolerance and persistence to these antibiotics, but this difference was not statistically significant. Finally, a K-12 strain expressing high levels of RpoS was compared with its isogenic RpoS-null counterpart, and no significant effect of RpoS was found.
CONCLUSION
Based on a representative collection of the species E. coli, RpoS was found to have a very small impact on antibiotic resistance, tolerance, or persistence.
Topics: Escherichia coli; Anti-Bacterial Agents; Drug Resistance, Microbial; Kanamycin; Aminoglycosides
PubMed: 38443813
DOI: 10.1186/s12866-024-03222-7 -
IScience Mar 2024Non-ribosomal peptide synthetases (NRPSs) assemble metabolites of medicinal and commercial value. Both serine and threonine figure prominently in these processes and...
Non-ribosomal peptide synthetases (NRPSs) assemble metabolites of medicinal and commercial value. Both serine and threonine figure prominently in these processes and separately can be converted to the additional NRPS building blocks 2,3-diaminopropionate (Dap) and 2,3-diaminobutyrate (Dab). Here we bring extensive bioinformatics, and experimentation to compose a unified view of the biosynthesis of these widely distributed non-canonical amino acids that both derive by pyridoxal-mediated β-elimination of the activated -phosphorylated substrates followed by β-addition of an amine donor. By examining monobactam biosynthesis in and in species where it is silent, we show that (2,3)-Dab synthesis depends on an l-threonine kinase (DabA), a β-replacement reaction with l-aspartate (DabB) and an argininosuccinate lyase-like protein (DabC). The growing clinical importance of monobactams to both withstand Ambler Class B metallo-β-lactamases and retain their antibiotic activity make reprogrammed precursor and NRPS synthesis of modified monobactams a feasible and attractive goal.
PubMed: 38433893
DOI: 10.1016/j.isci.2024.109202 -
The Lancet. Microbe Apr 2024Antimicrobials cause perturbations in the composition and diversity of the host microbiome. We aimed to compare gut microbiome perturbations caused by oral tebipenem... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Antimicrobials cause perturbations in the composition and diversity of the host microbiome. We aimed to compare gut microbiome perturbations caused by oral tebipenem pivoxil hydrobromide (a novel carbapenem) and by amoxicillin-clavulanic acid (an orally administered β-lactam-β-lactam inhibitor combination widely used in clinical practice).
METHODS
We did a phase 1, single-centre, randomised, parallel-group, active-control trial to evaluate the effect of tebipenem pivoxil hydrobromide on the human gut microbiota. Healthy participants aged 18 years or older with no documented illnesses during recruitment were enrolled at Karolinska University Hospital (Stockholm, Sweden). Study participants were stratified by sex and block-randomised in a 1:1 ratio to treatment with either tebipenem pivoxil hydrobromide (600 mg orally every 8 h) or amoxicillin-clavulanic acid (500 mg amoxicillin and 125 mg clavulanic acid orally every 8 h). The study included 10 days of treatment (days 1-10) and four follow-up visits (days 14, 21, 90, and 180). The trial was open-label for clinical investigators and patients, but masked for microbiology investigators. Faecal samples were collected at all visits. Sequencing of 16S rDNA was used to measure the diversity metrics, and quantitative culture to quantify selected taxa. The primary outcomes were changes in the α and β diversity and log count of colony-forming units for selected taxa between samples compared with baseline (day 1), and whether any changes reverted during the follow-up period. The analyses were done in the intention-to-treat population. This study was registered with ClinicalTrials.gov (NCT04376554).
FINDINGS
The study was conducted between Jan 23, 2020, and April 6, 2021. 49 volunteers were screened for eligibility, among whom 30 evaluable participants (14 men and 16 women) were assigned: 15 (50%) to the tebipenem pivoxil hydrobromide group and 15 (50%) to the amoxicillin-clavulanic acid group. Baseline characteristics were similar between groups. Complete follow-up was available for all participants, and all participants except one completed treatment as assigned. The diversity metrics showed significant changes from baseline during the treatment period. Significant decreases in richness were observed on days 4-10 (p≤0·0011) in the amoxicillin-clavulanic acid group and on days 4-14 (p≤0·0019) in the tebipenem pivoxil hydrobromide group. Similarly, evenness was significantly decreased during treatment in the amoxicillin-clavulanic acid group (day 4, p=0·030) and the tebipenem pivoxil hydrobromide group (days 4-10, p<0·0001) compared with baseline. Quantitative cultures showed significant decreases in Enterobacterales (days 4-7, p≤0·0030), Enterococcus spp (days 4-14, p=0·025 to p<0·0001), Bifidobacterium spp (days 2-4, p≤0·026), and Bacteroides spp (days 4-10, p≤0·030) in the tebipenem pivoxil hydrobromide group. Similarly, in amoxicillin-clavulanic acid recipients, significant changes were observed in Enterobacterales (days 4-10, p≤0·048), Bifidobacterium spp (days 2-4, p≤0·013), and Lactobacillus spp (days 2-4, p≤0·020). Samples from the follow-up period were not significantly different from those at baseline in β diversity analysis (PERMANOVA, p>0·99). By the end of the study, no significant change was observed compared with baseline in either group. There were no deaths or severe adverse events.
INTERPRETATION
The impact of tebipenem pivoxil hydrobromide on the gut microbiome was similar to that of amoxicillin-clavulanic acid. The safety of antibiotic use with regard to the microbiome should be given attention, as dysbiosis is associated with health and disease.
FUNDING
Spero Therapeutics.
Topics: Male; Adult; Humans; Female; Gastrointestinal Microbiome; Amoxicillin-Potassium Clavulanate Combination; Sweden; Anti-Bacterial Agents; Monobactams; Carbapenems
PubMed: 38432233
DOI: 10.1016/S2666-5247(23)00360-9 -
Antimicrobial Agents and Chemotherapy Apr 2024We evaluated the activity of meropenem-vaborbactam plus aztreonam (MEV-ATM) against 140 metallo-β-lactamase (MBL)-producing isolates. Among them, 25 isolates (17.9%)...
We evaluated the activity of meropenem-vaborbactam plus aztreonam (MEV-ATM) against 140 metallo-β-lactamase (MBL)-producing isolates. Among them, 25 isolates (17.9%) displayed minimum inhibitory concentrations (MIC) ≥ 8 µg/mL, while 112 (80.0%) had MIC ≤ 2 µg/mL. Genomic analysis and subsequent gene cloning experiments revealed OmpK36 134-135GD-insertion and increased carbapenemase gene ( and ) copy numbers are the main factors responsible for MEV-ATM non-susceptibility. Notably, MEV-ATM is actively against aztreonam-avibactam-resistant mutants due to CMY-16 mutations.
Topics: Meropenem; Aztreonam; Anti-Bacterial Agents; Klebsiella pneumoniae; beta-Lactamases; Drug Combinations; Microbial Sensitivity Tests; Azabicyclo Compounds; Boronic Acids
PubMed: 38426743
DOI: 10.1128/aac.01346-23 -
Pediatric Allergy and Immunology :... Mar 2024Allergy to beta-lactam antibiotics (BLA) is frequently suspected in children, but a drug provocation test (DPT) rules it out in over 90% of cases. Direct oral DPT...
BACKGROUND
Allergy to beta-lactam antibiotics (BLA) is frequently suspected in children, but a drug provocation test (DPT) rules it out in over 90% of cases. Direct oral DPT (DODPT), without skin or other previous tests, is increasingly been used to delabel non-immediate BLA reactions. This real-world study aimed to assess the safety and effectiveness of DODPT in children with immediate and non-immediate reactions to BLAs.
METHODS
Ambispective registry study in children (<15 years), attended between 2016 and 2023 for suspected BLA allergy in 15 hospitals in Spain that routinely perform DODPT.
RESULTS
The study included 2133 patients with generally mild reactions (anaphylaxis 0.7%). Drug provocation test with the implicated BLA was performed in 2014 patients (94.4%): 1854 underwent DODPT (86.9%, including 172 patients with immediate reactions). One hundred forty-five (7.2%) had symptoms associated with DPT, although only four reactions were severe: two episodes of anaphylaxis and two of drug-induced enterocolitis syndrome, which resolved rapidly with treatment. Of the 141 patients with mild reactions in the first DPT, a second DPT was considered in 87 and performed in 57, with 52 tolerating it without symptoms. Finally, BLA allergy was ruled out in 90.9% of the sample, confirmed in 3.4%, and remained unverified, usually due to loss to follow-up, in 5.8%.
CONCLUSIONS
Direct oral DPT is a safe, effective procedure even in immediate mild reactions to BLA. Many reactions observed in DPT are doubtful and require confirmation. Severe reactions are exceptional and amenable to treatment. Direct oral DPT can be considered for BLA allergy delabeling in pediatric primary care.
Topics: Child; Humans; beta-Lactams; Anti-Bacterial Agents; Skin Tests; Anaphylaxis; Drug Hypersensitivity; Monobactams
PubMed: 38425150
DOI: 10.1111/pai.14096 -
PLoS Pathogens Feb 2024The host environment is of critical importance for antibiotic efficacy. By impacting bacterial machineries, stresses encountered by pathogens during infection promote...
The host environment is of critical importance for antibiotic efficacy. By impacting bacterial machineries, stresses encountered by pathogens during infection promote the formation of phenotypic variants that are transiently insensitive to the action of antibiotics. It is assumed that these recalcitrant bacteria-termed persisters-contribute to antibiotic treatment failure and relapsing infections. Recently, we demonstrated that host reactive nitrogen species (RNS) transiently protect persisters against the action of β-lactam antibiotics by delaying their regrowth within host cells. Here, we discovered that RNS intoxication of persisters also collaterally sensitizing them to fluoroquinolones during infection, explaining the higher efficiency of fluoroquinolones against intramacrophage Salmonella. By reducing bacterial respiration and the proton-motive force, RNS inactivate the AcrAB efflux machinery of persisters, facilitating the accumulation of fluoroquinolones intracellularly. Our work shows that target inactivity is not the sole reason for Salmonella persisters to withstand antibiotics during infection, with active efflux being a major contributor to survival. Thus, understanding how the host environment impacts persister physiology is critical to optimize antibiotics efficacy during infection.
Topics: Anti-Bacterial Agents; Biological Transport; Fluoroquinolones; Monobactams; Proton-Motive Force; Osteosclerosis; Exophthalmos; Abnormalities, Multiple; Cleft Palate; Microcephaly
PubMed: 38421944
DOI: 10.1371/journal.ppat.1012033 -
Journal of Hazardous Materials May 2024Non-antibiotic substances have been found to contribute to the spread of antibiotic resistance. Bromophenols (BPs) are special anti-bacterial substances obtained from...
Non-antibiotic substances have been found to contribute to the spread of antibiotic resistance. Bromophenols (BPs) are special anti-bacterial substances obtained from seaweed. This study explored the modulatory effect of trace BPs from a live seaweed on the antibiotic resistance of pathogenic Vibrio (V.) strains. A hydroponic solution of Ulva fasciata was found to contain trace levels (9-333 μg L) of 2,4,6-tribromophenol (TBP), a typical BP. TBP at a concentration of 165 μg L significantly increased the inhibition zone diameter of widely used β-lactam antibiotics (amoxicillin and ampicillin) against V. alginolyticus M7 (Va. M7) and V. parahaemolyticus M3 (Vp. M3) as well as reduced the minimum inhibitory concentration by 2-4 fold against Va. M7. Whole genome re-sequencing analysis demonstrated that Va. M3 (53-60) had more mutant genes than Vp. M7 (44) in β-lactam resistance pathway. Transcriptome sequencing analysis, along with verification through RT-qPCR, further showed that oligopeptide permease (opp) was the only differentially expressed gene (DEG) among the mutated genes in the β-lactam resistance pathway. The opp transport activity and membrane permeability of Vibrio were both enhanced at 165 μg L of TBP, and the ability of biofilm formation was also decreased. Thus, antibiotics resistance improvement of Vibrio by TBP was potentially related with the promoted opp transport activity, membrane permeability and inhibited biofilm formation.
Topics: Anti-Bacterial Agents; beta Lactam Antibiotics; Seaweed; Vibrio; beta-Lactam Resistance; Monobactams; Edible Seaweeds; Phenols; Ulva
PubMed: 38417370
DOI: 10.1016/j.jhazmat.2024.133774 -
Antimicrobial Agents and Chemotherapy Apr 2024The impact of penicillin-binding protein 3 (PBP3) modifications that may be identified in was evaluated with respect to susceptibility to β-lactam/β-lactamase...
Effect of modification of penicillin-binding protein 3 on susceptibility to ceftazidime-avibactam, imipenem-relebactam, meropenem-vaborbactam, aztreonam-avibactam, cefepime-taniborbactam, and cefiderocol of strains producing broad-spectrum β-lactamases.
The impact of penicillin-binding protein 3 (PBP3) modifications that may be identified in was evaluated with respect to susceptibility to β-lactam/β-lactamase inhibitor combinations including ceftazidime-avibactam, imipenem-relebactam, meropenem-vaborbactam, aztreonam-avibactam, cefepime-taniborbactam, and to cefiderocol. A large series of recombinant strains producing broad-spectrum β-lactamases was evaluated. While imipenem-relebactam showed a similar activity regardless of the PBP3 background, susceptibility to other molecules tested was affected at various levels. This was particularly the case for ceftazidime-avibactam, aztreonam-avibactam, and cefepime-taniborbactam.
Topics: Aztreonam; Meropenem; Cefiderocol; Cefepime; Penicillin-Binding Proteins; Escherichia coli; beta-Lactamases; Anti-Bacterial Agents; Azabicyclo Compounds; Drug Combinations; Imipenem; Microbial Sensitivity Tests; Borinic Acids; Boronic Acids; Carboxylic Acids; Ceftazidime
PubMed: 38415988
DOI: 10.1128/aac.01548-23 -
Acta Anaesthesiologica Scandinavica Apr 2024Antibiotic concentration target attainment is known to be poor in critically ill patients. Dose adjustment is recommended in patients with altered clearance, obesity and... (Observational Study)
Observational Study
INTRODUCTION
Antibiotic concentration target attainment is known to be poor in critically ill patients. Dose adjustment is recommended in patients with altered clearance, obesity and those with bacterial species with intermediate susceptibility. The aim of this study was to investigate the variation of antibiotic concentration in critically ill patients with standard or adjusted dosing regimens.
METHODS
The concentration of three beta-lactam antibiotics used in the intensive care unit (ICU) setting, cefotaxime, piperacillin/tazobactam, and meropenem, was measured in patients with confirmed or suspected infection. Mid-dose and trough values were collected during a single dosing interval. The pharmacokinetic endpoints were a free antibiotic concentration that, during the whole dosing interval, was above MIC (100% ƒT > MIC, primary endpoint) or above four times MIC (100% ƒT > 4MIC, secondary endpoint). Non-species related MIC breakpoints were used (1 mg/L for cefotaxime, 8 mg/L for piperacillin/tazobactam, and 2 mg/L for meropenem).
RESULTS
We included 102 patients (38 cefotaxime, 30 piperacillin/tazobactam, and 34 meropenem) at a single ICU, with a median age of 66 years. In total, 73% were males, 40% were obese (BMI ≥30) and the median SAPS 3 score was 63 points. Of all patients, 78 patients (76%) reached the primary endpoint (100%ƒT > MIC), with 74% for cefotaxime, 67% for piperacillin/tazobactam and 88% for meropenem. Target attainment for 100% ƒT > 4MIC was achieved in 40 (39%) patients, overall, with 34% for cefotaxime, 30% for piperacillin/tazobactam and 53% for meropenem. In patients with standard dose 71% attained 100%ƒT > MIC and 37% for 100%ƒT > 4MIC. All patients with reduced dose attained 100%ƒT > MIC and 27% attained 100% ƒT > 4MIC. In patients with increased dose 79% attained 100%ƒT > MIC and 48% 100%ƒT > 4MIC respectively.
CONCLUSIONS
Beta-lactam antibiotics concentration vary widely in critically ill patients. The current standard dosing regimens employed during the study were not sufficient to reach 100% ƒT > MIC in approximately a quarter of the patients. In patients where dose adjustment was performed, the group with increased dose also had low target attainment, as opposed to patients with dose reduction, who all reached target. This suggests the need for further individualization of dosing where therapeutic drug monitoring can be an alternative to further increase target attainment.
Topics: Male; Humans; Aged; Female; Meropenem; Piperacillin; Critical Illness; Anti-Bacterial Agents; Piperacillin, Tazobactam Drug Combination; Monobactams; Cefotaxime; beta Lactam Antibiotics
PubMed: 38407447
DOI: 10.1111/aas.14382 -
Poultry Science Apr 2024Riemerella anatipestifer (R. anatipestifer) is a highly pathogenic and complex serotypes waterfowl pathogen with inherent resistance to multiple antibiotics. This study...
Riemerella anatipestifer (R. anatipestifer) is a highly pathogenic and complex serotypes waterfowl pathogen with inherent resistance to multiple antibiotics. This study was aimed to investigate the antibiotic resistance characteristics and genomic features of R. anatipestifer isolates in Anhui Province, China in 2023. A total of 287 cases were analysed from duck farms and goose farms, and the R. anatipestifer isolates were subjected to drug resistance tests for 30 antimicrobials. Whole genome sequencing (WGS) and bioinformatics analysis were performed on the bacterial genomes, targeting the β-lactam resistance genes. The results showed that a total of 74 isolates of R. anatipestifer were isolated from 287 cases, with a prevalence of 25.8%. The antimicrobial susceptibility testing (AST) revealed that all the 74 isolates were resistant to multiple drugs, ranging from 13 to 26 kinds of drugs. Notably, these isolates showed significant resistance to aminoglycosides and macrolides, which are also commonly used in clinical practices. Data revealed the presence of several β-lactamase-related genes among the isolates, including a novel bla variant (16.2%), the class A extended-spectrum β-lactamase bla (12.2%), and a bla variant (98.6%). Functional analysis of the variants bla and bla showed that the bla variant exhibited activity against various β-lactam antibiotics while their occurrence in R. anatipestifer were not common. The bla variant, on the other hand, did not perform any β-lactam antibiotic resistance. Furthermore, we observed that bla could undergo horizontal transmission among different bacteria via the insertion sequence IS982. In conclusion, this study delves into the high prevalence of R. anatipestifer infection in waterfowl in Anhui, China. The isolated strains exhibit severe drug resistance issues, closely associated with the prevalence of antibiotic resistance genes (ARG). Additionally, our research investigates the β-lactam antibiotic resistance mechanism in R. anatipestifer.
Topics: Animals; Anti-Bacterial Agents; Chickens; Riemerella; Monobactams; beta-Lactam Resistance; beta Lactam Antibiotics; beta-Lactamases; Ducks
PubMed: 38387287
DOI: 10.1016/j.psj.2024.103490