-
Microbiology Spectrum Jun 2024Carbapenem-resistant Enterobacterales represent a major health threat and have few approved therapeutic options. Enterobacterales isolates were collected from...
UNLABELLED
Carbapenem-resistant Enterobacterales represent a major health threat and have few approved therapeutic options. Enterobacterales isolates were collected from hospitalized inpatients from 49 sites in six European countries (1 January-31 December 2020) and underwent susceptibility testing to cefiderocol and β-lactam/β-lactamase inhibitor combinations. Meropenem-resistant (MIC >8 mg/L) and cefiderocol-susceptible isolates were analyzed by PCR, and cefiderocol-resistant isolates by whole-genome sequencing, to identify resistance mechanisms. Overall, 1,909 isolates (including 970 spp., 382 , and 244 spp.) were collected, commonly from bloodstream infections (43.6%). Cefiderocol susceptibility was higher than approved β-lactam/β-lactamase inhibitor combinations and largely comparable to cefepime-taniborbactam and aztreonam-avibactam against all Enterobacterales (98.1% vs 78.1%-97.4% and 98.7%-99.1%, respectively) and Enterobacterales resistant to meropenem ( = 148, including 125 spp.; 87.8% vs 0%-71.6% and 93.2%-98.6%, respectively), β-lactam/β-lactamase inhibitor combinations (66.7%-92.1% vs 0%-88.1% and 66.7%-97.9%, respectively), and to both meropenem and β-lactam/β-lactamase inhibitor combinations (61.9%-65.9% vs 0%-20.5% and 76.2%-97.7%, respectively). Susceptibilities to approved and developmental β-lactam/β-lactamase inhibitor combinations against cefiderocol-resistant Enterobacterales ( = 37) were 10.8%-56.8% and 78.4%-94.6%, respectively. Most meropenem-resistant Enterobacterales harbored carbapenemase (110/148) genes, although metallo-β-lactamase (35/148) and oxacillinase (OXA) carbapenemase (6/148) genes were less common; cefiderocol susceptibility was retained in β-lactamase producers, other than NDM, AmpC, and non-carbapenemase OXA producers. Most cefiderocol-resistant Enterobacterales had multiple resistance mechanisms, including ≥1 iron uptake-related mutation (37/37), carbapenemase gene (33/37), and mutation (24/37). The susceptibility to cefiderocol was higher than approved β-lactam/β-lactamase inhibitor combinations against European Enterobacterales, including meropenem- and β-lactam/β-lactamase inhibitor combination-resistant isolates.
IMPORTANCE
This study collected a notably large number of Enterobacterales isolates from Europe, including meropenem- and β-lactam/β-lactamase inhibitor combination-resistant isolates against which the activities of cefiderocol and developmental β-lactam/β-lactamase inhibitor combinations were directly compared for the first time. The MIC breakpoint for high-dose meropenem was used to define meropenem resistance, so isolates that would remain meropenem resistant with doses clinically available to patients were included in the data. Susceptibility to cefiderocol, as a single active compound, was high against Enterobacterales and was higher than or comparable to available β-lactam/β-lactamase inhibitor combinations. These results provide insights into the treatment options for infections due to Enterobacterales with resistant phenotypes. Early susceptibility testing of cefiderocol in parallel with β-lactam/β-lactamase inhibitor combinations will allow patients to receive the most appropriate treatment option(s) available in a timely manner. This is particularly important when options are more limited, such as against metallo-β-lactamase-producing Enterobacterales.
PubMed: 38904361
DOI: 10.1128/spectrum.04181-23 -
RSC Medicinal Chemistry Jun 2024New Delhi-β-lactamase-1 (NDM-1) is a type of metal-β-lactamase. NDM-1-expressing bacteria can spread rapidly across the globe plasmid transfer, which greatly...
New Delhi-β-lactamase-1 (NDM-1) is a type of metal-β-lactamase. NDM-1-expressing bacteria can spread rapidly across the globe plasmid transfer, which greatly undermines the clinical efficacy of the carbapenem. Research on NDM-1 inhibitors has attracted extensive attention. However, there are currently no clinically available NDM-1 inhibitors. Our research group has reported that 1,2-benzisoselenazol-3(2)-one derivatives as covalent NDM-1 inhibitors can restore the efficacy of meropenem (Mem) against NDM-1 producing strains. In this study, 22 compounds were designed and synthesized, which restored the Mem susceptibility of NDM-1-expressing and its minimum inhibitory concentration (MIC) was reduced by 2-16 times. Representative compound A4 showed significant synergistic antibacterial activity against NDM-1-producing carbapenem-resistant Enterobacteriaceae (CRE) isolates. The NDM-1 enzyme inhibitory activity test showed that the IC was 1.26 ± 0.37 μM, which had low cytotoxicity. When combined with meropenem, it showed good combined antibacterial activity. Electrospray ionization mass spectrometry (ESI-MS) analysis demonstrates that compound A4 covalently binds to NDM-1 enzyme. In summary, compound A4 is a potent NDM-1 covalent inhibitor and provides a potential lead compound for drug development in resistant bacteria.
PubMed: 38903944
DOI: 10.1039/d4md00031e -
Frontiers in Cellular and Infection... 2024Ceftazidime/avibactam (CZA) is indicated against multidrug-resistant , particularly those that are carbapenem resistant. CZA resistance in producing PER, a class A...
INTRODUCTION
Ceftazidime/avibactam (CZA) is indicated against multidrug-resistant , particularly those that are carbapenem resistant. CZA resistance in producing PER, a class A extended-spectrum β-lactamase, has been well documented . However, data regarding clinical isolates are scarce. Our aim was to analyze the contribution of PER to CZA resistance in non-carbapenemase-producing clinical isolates that were ceftazidime and/or carbapenem non-susceptible.
METHODS
Antimicrobial susceptibility was determined through agar dilution and broth microdilution, while gene was screened through PCR. All PER-positive isolates and five PER-negative isolates were analyzed through Whole Genome Sequencing. The mutational resistome associated to CZA resistance was determined through sequence analysis of genes coding for PBPs 1b, 3 and 4, MexAB-OprM regulators MexZ, MexR, NalC and NalD, AmpC regulators AmpD and AmpR, and OprD porin. Loss of gene was induced in a PER-positive isolate by successive passages at 43°C without antibiotics.
RESULTS
Twenty-six of 287 isolates studied (9.1%) were CZA-resistant. Thirteen of 26 CZA-resistant isolates (50%) carried . One isolate carried but was CZA-susceptible. PER-producing isolates had significantly higher MICs for CZA, amikacin, gentamicin, ceftazidime, meropenem and ciprofloxacin than non-PER-producing isolates. All PER-producing isolates were ST309 and their gene was associated to ISCR1, an insertion sequence known to mobilize adjacent DNA. PER-negative isolates were classified as ST41, ST235 (two isolates), ST395 and ST253. PER-negative isolates carried genes for narrow-spectrum β-lactamases and the mutational resistome showed that all isolates had one major alteration in at least one of the genes analyzed. Loss of gene restored susceptibility to CZA, ceftolozane/tazobactam and other β-lactamsin the evolved isolate.
DISCUSSION
PER-3-producing ST309 is a successful multidrug-resistant clone with gene implicated in resistance to CZA and other β-lactams.
Topics: Ceftazidime; Pseudomonas aeruginosa; Azabicyclo Compounds; Microbial Sensitivity Tests; Humans; Drug Combinations; beta-Lactamases; Anti-Bacterial Agents; Pseudomonas Infections; Bacterial Proteins; Drug Resistance, Multiple, Bacterial; Chile; Whole Genome Sequencing; Mutation
PubMed: 38903939
DOI: 10.3389/fcimb.2024.1410834 -
Frontiers in Microbiology 2024has strong drug resistance and can tolerate a variety of antibiotics, which is a major problem in the management of antibiotic-resistant infections. Direct prediction...
OBJECTIVE
has strong drug resistance and can tolerate a variety of antibiotics, which is a major problem in the management of antibiotic-resistant infections. Direct prediction of multi-drug resistance (MDR) resistance phenotypes of isolates and clinical samples by genotype is helpful for timely antibiotic treatment.
METHODS
In the study, whole genome sequencing (WGS) data of 494 isolates were used to screen key anti-microbial resistance (AMR)-associated genes related to imipenem (IPM), meropenem (MEM), piperacillin/tazobactam (TZP), and levofloxacin (LVFX) resistance in by comparing genes with copy number differences between resistance and sensitive strains. Subsequently, for the direct prediction of the resistance of to four antibiotics by the AMR-associated features screened, we collected 74 positive sputum samples to sequence by metagenomics next-generation sequencing (mNGS), of which 1 sample with low quality was eliminated. Then, we constructed the resistance prediction model.
RESULTS
We identified 93, 88, 80, 140 AMR-associated features for IPM, MEM, TZP, and LVFX resistance in . The relative abundance of AMR-associated genes was obtained by matching mNGS and WGS data. The top 20 features with importance degree for IPM, MEM, TZP, and LVFX resistance were used to model, respectively. Then, we used the random forest algorithm to construct resistance prediction models of , in which the areas under the curves of the IPM, MEM, TZP, and LVFX resistance prediction models were all greater than 0.8, suggesting these resistance prediction models had good performance.
CONCLUSION
In summary, mNGS can predict the resistance of by directly detecting AMR-associated genes, which provides a reference for rapid clinical detection of drug resistance of pathogenic bacteria.
PubMed: 38903781
DOI: 10.3389/fmicb.2024.1413434 -
BioRxiv : the Preprint Server For... May 2024Treatment of pulmonary disease requires multiple antibiotics including intravenous β-lactams (e.g., imipenem, meropenem). produces a β-lactamase (Bla) that...
Treatment of pulmonary disease requires multiple antibiotics including intravenous β-lactams (e.g., imipenem, meropenem). produces a β-lactamase (Bla) that inactivates β-lactam drugs but less efficiently carbapenems. Due to intrinsic and acquired resistance in and poor clinical outcomes, it is critical to understand the development of antibiotic resistance both within the host and in the setting of outbreaks. We compared serial longitudinally collected subsp. isolates from the index case of a CF center outbreak and four outbreak-related strains. We found strikingly high imipenem resistance in the later patient isolates, including the outbreak strain (MIC >512 μg/ml). The phenomenon was recapitulated upon exposure of intracellular bacteria to imipenem. Addition of the β-lactamase inhibitor avibactam abrogated the resistant phenotype. Imipenem resistance was caused by an increase in β-lactamase activity and increased mRNA level. Concurrent increase in transcription of preceding gene indicated upregulation of the entire operon in the resistant strains. Deletion of the porin coincided with the first increase in MIC (from 8 to 32 μg/ml). A frameshift mutation in responsible for the rough colony morphology, and a SNP in ATP-dependent helicase co-occurred with the second increase in MIC (from 32 to 256 μg/ml). Increased Bla expression and enzymatic activity may have been due to altered regulation of the operon by the mutated HrpA alone, or in combination with other genes described above. This work supports using carbapenem/β-lactamase inhibitor combinations for treating , particularly imipenem resistant strains.
PubMed: 38903073
DOI: 10.1101/2024.05.08.593223 -
BMC Microbiology Jun 2024In Addis Ababa, Ethiopia, open ditches along innner roads in residential areas serve to convey domestic wastewater and rainwater away from residences. Contamination of...
BACKGROUND
In Addis Ababa, Ethiopia, open ditches along innner roads in residential areas serve to convey domestic wastewater and rainwater away from residences. Contamination of drinking water by wastewater through faulty distribution lines could expose households to waterborne illnesses. This prompted the study to assess the microbiological safety of wastewater and drinking water in Addis Ababa, identify the pathogens therein, and determine their antibiotic resistance patterns.
RESULTS VIBRIO CHOLERAE
O1, mainly Hikojima serotype, was isolated from 23 wastewater and 16 drinking water samples. Similarly, 19 wastewater and 10 drinking water samples yielded Escherichia coli O157:H7. V. cholerae O1 were 100% resistant to the penicillins (Amoxacillin and Ampicillin), and 51-82% were resistant to the cephalosporins. About 44% of the V. cholerae O1 isolates in this study were Extended Spectrum Beta-Lactamase (ESBL) producers. Moreover, 26% were resistant to Meropenem. Peperacillin/Tazobactam was the only effective β-lactam antibiotic against V. cholerae O1. V. cholerae O1 isolates showed 37 different patterns of multiple resistance ranging from a minimum of three to a maximum of ten antimicrobials. Of the E. coli O157:H7 isolates, 71% were ESBL producers. About 96% were resistant to Ampicillin. Amikacin and Gentamicin were very effective against E. coli O157:H7 isolates. The isolates from wastewater and drinking water showed multiple antibiotic resistance against three to eight antibiotic drugs.
CONCLUSIONS
Open ditches for wastewater conveyance along innner roads in residence areas and underground faulty municipal water distribution lines could be possible sources for V. cholerae O1 and E. coli O157:H7 infections to surrounding households and for dissemination of multiple drug resistance in humans and, potentially, the environment.
Topics: Ethiopia; Vibrio cholerae O1; Wastewater; Escherichia coli O157; Anti-Bacterial Agents; Drinking Water; Microbial Sensitivity Tests; Drug Resistance, Multiple, Bacterial; beta-Lactamases; Humans; Water Microbiology
PubMed: 38902619
DOI: 10.1186/s12866-024-03302-8 -
BMC Infectious Diseases Jun 2024Phytobacter diazotrophicus (P. diazotrophicus) is an opportunistic pathogen that causes nosocomial outbreaks and sepsis. However, there are no reports of P....
BACKGROUND
Phytobacter diazotrophicus (P. diazotrophicus) is an opportunistic pathogen that causes nosocomial outbreaks and sepsis. However, there are no reports of P. diazotrophicus isolated from human blood in China.
CASE PRESENTATION
A 27-day-old female infant was admitted to our hospital with fever and high bilirubin levels. The clinical features included jaundice, abnormal coagulation, cholestasis, fever, convulsions, weak muscle tension, sucking weakness, ascites, abnormal tyrosine metabolism, cerebral oedema, abnormal liver function, clavicle fracture, and haemolytic anaemia. The strain isolated from the patient's blood was identified as P. diazotrophicus by whole-genome sequencing (WGS). Galactosemia type 1 (GALAC1) was diagnosed using whole-exome sequencing (WES). Based on drug sensitivity results, 10 days of anti-infective treatment with meropenem combined with lactose-free milk powder improved symptoms.
CONCLUSION
P. diazotrophicus was successfully identified in a patient with neonatal sepsis combined with galactosemia. Galactosemia may be an important factor in neonatal sepsis. This case further expands our understanding of the clinical characteristics of GALAC1.
Topics: Humans; Female; China; Galactosemias; Sepsis; Infant, Newborn; Anti-Bacterial Agents; Meropenem; Whole Genome Sequencing; Gammaproteobacteria
PubMed: 38898413
DOI: 10.1186/s12879-024-09458-y -
Environmental Pollution (Barking, Essex... Jun 2024We compared the ability of one emergent (Sagittaria montevidensis), two floating (Salvinia minima and Lemna gibba), and one heterophyllous species (Myriophyllum...
We compared the ability of one emergent (Sagittaria montevidensis), two floating (Salvinia minima and Lemna gibba), and one heterophyllous species (Myriophyllum aquaticum) to simultaneously remove sulfamethoxazole, sulfadiazine, ciprofloxacin, enrofloxacin, norfloxacin, levofloxacin, oxytetracycline, tetracycline, doxycycline, azithromycin, amoxicillin, and meropenem from wastewater in a mesocosm-scale constructed wetland over 28 days. Antibiotic concentrations in plants and effluent were analyzed using an LC-MS/MS to assess the removal rates and phytoremediation capacities. M. aquaticum did not effectively mitigate contamination due to poor tolerance and survival in effluent conditions. S. minima and L. gibba demonstrated superior efficiency, reducing the antibiotic concentrations to undetectable levels within 14 days, while S. montevidensis achieved this result by day 28. Floating macrophytes emerge as the preferable choice for remediation of antibiotics compared to emergent and heterophyllous species. Antibiotics were detected in plant tissues at concentrations ranging from 0.32 to 29.32 ng g fresh weight, highlighting macrophytes' ability to uptake and accumulate these contaminants. Conversely, non-planted systems exhibited a maximum removal rate of 65%, underscoring the persistence of these molecules in natural environments, even after the entire experimental period. Additionally, macrophytes improved effluent quality regardless of species by reducing total soluble solids and phosphate concentrations and mitigating ecotoxicological effects. This study underscores the potential of using macrophytes in wastewater treatment plants to enhance overall efficiency and prevent environmental contamination by antibiotics, thereby mitigating the harmful impact on biota and antibiotic resistance. Selecting appropriate plant species is crucial for successful phytoremediation in constructed wetlands, and actual implementation is essential to validate their effectiveness and practical applicability.
PubMed: 38897277
DOI: 10.1016/j.envpol.2024.124376 -
British Journal of Biomedical Science 2024Within cystic fibrosis microbiology, there is often mismatch between the antibiotic susceptibility result of an isolated bacterial pathogen and the clinical outcome,...
Case Report: The Conundrum of What to Pick? Antibiotic Susceptibility Variability in in Cystic Fibrosis: Implications for Antibiotic Susceptibility Testing and Treatment.
Within cystic fibrosis microbiology, there is often mismatch between the antibiotic susceptibility result of an isolated bacterial pathogen and the clinical outcome, when the patient is treated with the same antibiotic. The reasoning for this remains largely elusive. Antibiotic susceptibility to four antibiotics (ceftazidime, meropenem, minocycline and trimethoprim-sulfamethoxazole) was determined in consecutive isolates ( = 11) from an adult cystic fibrosis patient, over a 63 month period. Each isolate displayed its own unique resistotype. The first isolate was sensitive to all four antibiotics, in accordance with Clinical and Laboratory Standards Institute methodology and interpretative criteria. Resistance was first detected at four months, showing resistance to ceftazidime and meropenen and intermediate resistance to minocycline and trimethoprim-sulfamethoxazole. Pan resistance was first detected at 18 months (resistotype IV), with three resistotypes (I, II and III) preceding this complete resistotype. The bacterium continued to display further antibiotic susceptibility heterogeneity for the next 45 months, with the description of an additional seven resistotypes (resistotypes V-XI). The Relative Resistance Index of this bacterium over the 63 month period showed no relationship between the development of antibiotic resistance and time. Adoption of mathematical modelling employing multinomial distribution demonstrated that large numbers of individual colony picks (>40/sputum), would be required to be 78% confident of capturing all 11 resistotypes present. Such a requirement for large numbers of colony picks combined with antibiotic susceptibility-related methodological problems creates a conundrum in biomedical science practice, in providing a robust assay that will capture antibiotic susceptibility variation, be pragmatic and cost-effective to deliver as a pathology service, but have the reliability to help clinicians select appropriate antibiotics for their patients. This study represents an advance in biomedical science as it demonstrates potential variability in antibiotic susceptibility testing with . Respiratory physicians and paediatricians need to be made aware of such variation by biomedical scientists at the bench, so that clinicians can contextualise the significance of the reported susceptibility result, when selecting appropriate antibiotics for their cystic fibrosis patient. Furthermore, consideration needs to be given in providing additional guidance on the laboratory report to highlight this heterogeneity to emphasise the potential for misalignment between susceptibility result and clinical outcome.
Topics: Cystic Fibrosis; Humans; Anti-Bacterial Agents; Microbial Sensitivity Tests; Burkholderia cenocepacia; Burkholderia Infections; Adult; Drug Resistance, Bacterial
PubMed: 38895586
DOI: 10.3389/bjbs.2024.12749 -
Cureus May 2024Background and objective Urinary tract infections (UTIs) are a common infectious disease affecting people of various ages and genders and are prevalent in different...
The Prevalence of Multidrug-Resistant Uropathogenic Bacterial Profile With Antibiotic Susceptibility Patterns Among the Community and Hospitalized Patients During COVID Waves.
Background and objective Urinary tract infections (UTIs) are a common infectious disease affecting people of various ages and genders and are prevalent in different geographical locations. However, the way Gram-positive and Gram-negative (UTI) germs react to antibiotic treatment varies significantly. The coronavirus disease 2019 (COVID-19) pandemic has increased the frequency of secondary bacterial superinfection, leading to a spike in ongoing recommendations for antibiotic treatment, both therapeutic and preventative. In this study, we aimed to assess uropathogenic bacterial resistance and shed light on how COVID-19 epidemic waves influence the evolution of bacterial resistance. Materials and methods A cross-sectional study was conducted, assessing the different isolates of the uropathogen in all COVID-19 waves by using convenience sampling from August 2020 till the end of 2023. The VITEK-2 compact system employing industry-standard bacteriological tests to identify the bacteria and confirm their antibiotic susceptibility was utilized. Results Of the total 3877 patients, 381 (9.8%) and 3483 (89.8%) had positive and negative microbial growth, respectively. Of the 381 (9.8%) positive cases, 130 (34%) were male and 251 (65%) were female; 138 (43.3%) patients in the age range of 15-40 years developed sporadic UTIs attributed to Gram-negative bacteria. Alternatively, patients over 40 years had the highest prevalence rate (n = 180, 56.6%). The most common strains of Gram-negative and Gram-positive bacteria were and with278 (88.8%) and 13 (20.9%) cases respectively. People with Gram-negative bacteria who were not hospitalized were very resistant to trimethoprim/sulfamethoxazole (n = 219, 69.1%), cefotaxime (n = 193, 60.9%), ampicillin (n = 192, 60.6%), and amoxicillin/clavulanic acid (176, 55.5%). While high sensitivity to meropenem (n = 14, 4.4%) and imipenem (n = 13, 4.1%) was observed, hospitalized individuals had higher levels of resistance and great sensitivity to the same antibiotics. S. . were commonly present. Hospitalized patients were less sensitive to benzylpenicillin, ampicillin, and oxacillin, and there was a big rise in resistance to cefoxitin in the community. Conclusions In this study, Gram-negative germs among females were predominantly observed with extremely high multi-drug resistance (MDR). The most effective antibiotics against Gram-positive germs included linezolid, vancomycin, and nitrofurantin, while those against Gram-negative bacteria were meropenem and amikacin. Clinicians should be regularly updated and informed about antibiotic selection through routine monitoring of uropathogenic bacteria's susceptibility. Moreover, we recommend changes to the local antibiotic policy regarding the selection of UTIs; further multicentric and high-volume studies are required to gain deeper insights into the topic.
PubMed: 38894805
DOI: 10.7759/cureus.60613