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Frontiers in Microbiology 2022plasmids can mediate high-level antimicrobial resistance. The emergence of clinical isolates producing plasmid β-lactamases that can hydrolyze cephalosporins, the...
plasmids can mediate high-level antimicrobial resistance. The emergence of clinical isolates producing plasmid β-lactamases that can hydrolyze cephalosporins, the mainstay treatment for gonorrhea, may be a serious threat. In this work, strains producing plasmid-mediated broad- and extended-spectrum β-lactamases (ESBLs) were obtained , and their viability and β-lactam antibiotic susceptibility were studied. Artificial p and p plasmids were constructed by site-directed mutagenesis from a p plasmid isolated from a clinical isolate. Minimum inhibitory concentration (MIC) values for a series of β-lactam antibiotics, including benzylpenicillin, ampicillin, cefuroxime, ceftriaxone, cefixime, cefotaxime, cefepime, meropenem, imipenem, and doripenem, were determined. The strain carrying the p plasmid exhibited a high level of resistance to penicillins and second-fourth-generation cephalosporins (MIC ≥2 mg/L) but not to carbapenems (MIC ≤0.008 mg/L). However, this strain stopped growing after 6 h of culture. The reduction in viability was not associated with loss of the plasmid but can be explained by the presence of the plasmid itself, which requires additional reproduction costs, and to the expression of ESBLs, which can affect the structure of the peptidoglycan layer in the cell membrane. Cell growth was mathematically modeled using the generalized Verhulst equation, and the reduced viability of the plasmid-carrying strains compared to the non-plasmid-carrying strains was confirmed. The cell death kinetics of strains without the p plasmid in the presence of ceftriaxone can be described by a modified Chick-Watson law. The corresponding kinetics of the strain carrying the p plasmid reflected several processes: the hydrolysis of ceftriaxone by the TEM-20 β-lactamase and the growth and gradual death of cells. The demonstrated reduction in the viability of strains carrying the p plasmid probably explains the absence of clinical isolates of ESBL-producing .
PubMed: 35794921
DOI: 10.3389/fmicb.2022.896607 -
Biomedicines Jun 2022The inoculum effect (IE) is a well-known phenomenon with beta-lactams. At the same time, the IE has not been extensively studied with carbapenem/carbapenemase inhibitor...
The inoculum effect (IE) is a well-known phenomenon with beta-lactams. At the same time, the IE has not been extensively studied with carbapenem/carbapenemase inhibitor combinations. The antibiotic-to-inhibitor concentration ratio used in susceptibility testing can influence the in vitro activity of the combination. To explore the role of these factors, imipenem/relebactam and doripenem/relebactam MICs were estimated against six carbapenemase (KPC)-producing strains at standard inocula (SI) and high inocula (HI) by two methods: with a fixed relebactam concentration and with a fixed, pharmacokinetic-based carbapenem-to-relebactam concentration ratio. The combination MICs at HI, compared to SI, increased with most of the tested strains. However, the IE occurred with only two strains regardless of the MIC testing method. The relationship between the MICs at SI and the respective inoculum-induced MIC changes was observed when the MICs were estimated at pharmacokinetic-based carbapenem-to-relebactam concentration ratios. Thus, (1) IE was observed with both carbapenem/relebactam combinations regardless of the MIC testing method; however, IE was not observed frequently among tested strains. (2) At HI, carbapenem/relebactam combination MICs increased to levels associated with carbapenem resistance. (3) Combination MICs determined at pharmacokinetic-based carbapenem-to-inhibitor concentration ratios predict susceptibility elevations at HI in KPC-producing .
PubMed: 35740475
DOI: 10.3390/biomedicines10061454 -
Antibiotics (Basel, Switzerland) Jun 2022Background: The increasing prevalence of multidrug-resistant Enterobacteriaceae limits the range of active antimicrobial agents, thus worsening clinical outcomes. The...
Background: The increasing prevalence of multidrug-resistant Enterobacteriaceae limits the range of active antimicrobial agents, thus worsening clinical outcomes. The objective of this study was to identify the trends in antimicrobial resistance for Enterobacteriaceae in Russia using the databases for the International Network for Optimal Resistance Monitoring (INFORM) and Antimicrobial Testing Leadership and Surveillance (ATLAS) studies between 2012 and 2018. Methods: This subanalysis was performed for 3811 non-duplicate clinical isolates of Enterobacteriaceae to evaluate the in vitro activity of the main classes of antibiotics against relevant clinical isolates from hospitalized patients with complicated infections of different anatomical locations. Results: The lowest susceptibility was observed for colistin (0%), ampicillin (16.4%), and ampicillin/sulbactam (31.1%), whereas the best susceptibility was observed for all combinations containing avibactam (>96%). Among individual antimicrobials, doripenem (3.2%), tigecycline (1.6%), and meropenem (5.9%) exhibited the lowest resistance. Important trends included the decreasing resistance of Enterobacteriaceae to glycylcyclines and the increasing resistance to aminoglycosides and carbapenems. K. pneumoniae strains were most aggressive in terms of the percentage of strains having multidrug resistance (8.3−18.3%, depending on location) and the percentage of ESBL-positive strains (44.8−86.8%). Conclusions: The current patterns and trends of antimicrobial resistance in different bacterial species should be taken into consideration for timely updating of clinical guidelines and local treatment protocols to ensure effective antimicrobial therapy.
PubMed: 35740196
DOI: 10.3390/antibiotics11060790 -
The Journal of Biological Chemistry Jul 2022The evolution of multidrug resistance in Acinetobacter spp. increases the risk of our best antibiotics losing their efficacy. From a clinical perspective, the...
The evolution of multidrug resistance in Acinetobacter spp. increases the risk of our best antibiotics losing their efficacy. From a clinical perspective, the carbapenem-hydrolyzing class D β-lactamase subfamily present in Acinetobacter spp. is particularly concerning because of its ability to confer resistance to carbapenems. The kinetic profiles of class D β-lactamases exhibit variability in carbapenem hydrolysis, suggesting functional differences. To better understand the structure-function relationship between the carbapenem-hydrolyzing class D β-lactamase OXA-24/40 found in Acinetobacter baumannii and carbapenem substrates, we analyzed steady-state kinetics with the carbapenem antibiotics meropenem and ertapenem and determined the structures of complexes of OXA-24/40 bound to imipenem, meropenem, doripenem, and ertapenem, as well as the expanded-spectrum cephalosporin cefotaxime, using X-ray crystallography. We show that OXA-24/40 exhibits a preference for ertapenem compared with meropenem, imipenem, and doripenem, with an increase in catalytic efficiency of up to fourfold. We suggest that superposition of the nine OXA-24/40 complexes will better inform future inhibitor design efforts by providing insight into the complicated and varying ways in which carbapenems are selected and bound by class D β-lactamases.
Topics: Acinetobacter baumannii; Anti-Bacterial Agents; Bacterial Proteins; Carbapenems; Hydrolysis; Microbial Sensitivity Tests; Protein Conformation; Substrate Specificity; beta-Lactamases
PubMed: 35709986
DOI: 10.1016/j.jbc.2022.102127 -
Microbiology Spectrum Jun 2022Adoption of revised antimicrobial susceptibility breakpoints is often slow, potentially leading to underreporting of antimicrobial resistance. We compared...
A Multicenter Comparison of Carbapenem-Nonsusceptible Enterobacterales and Pseudomonas aeruginosa Rates in the US (2016 to 2020): Facility-Reported Rates versus Rates Based on Updated Clinical Laboratory and Standards Institute Breakpoints.
Adoption of revised antimicrobial susceptibility breakpoints is often slow, potentially leading to underreporting of antimicrobial resistance. We compared facility-reported rates of carbapenem nonsusceptibility (NS; intermediate or resistant) with NS rates based on current Clinical and Laboratory Standards Institute (CLSI) breakpoints for Enterobacterales or Pseudomonas aeruginosa isolates in ambulatory and inpatient adults in the BD Insights Research Database (US) from 2016 to 2020. Overall, 77.4% (937,926/1,211,845) and 90.6% (2,157,785/2,381,824) of nonduplicate Enterobacterales isolates with facility-reported susceptibility results had MIC data for ertapenem (ETP) and imipenem/meropenem/doripenem (IPM/MEM/DOR), respectively; 86.9% (255,844/294,426) of P. aeruginosa isolates had MIC data for IPM/MEM/DOR. Facility-reported susceptibility and susceptibility based on CLSI criteria resulted in comparable carbapenem susceptibility rates (99.3% versus 99.1% for ETP-susceptible Enterobacterales, 98.9% versus 98.4% for IPM/MEM/DOR-susceptible Enterobacterales, and 84.9% versus 83.3% for IPM/MEM/DOR-susceptible P. aeruginosa). However, compared with CLSI criteria, facilities underreported Enterobacterales- and IPM/MEM/DOR-NS isolates by 18.8% and 26.5%, respectively, and P. aeruginosa IPM/MEM/DOR-NS isolates by 9.8%. Underreporting was observed for both intermediate and resistant isolates. Our data suggest that delayed adoption of revised breakpoints has a small but potentially important impact on reported rates of antimicrobial resistance. Facilities should be aware of local epidemiology, evaluate potential underreporting of resistance, and assess the related clinical impact. Clinicians often base antimicrobial therapeutic decisions on laboratory determinations of pathogen susceptibility to an antibiotic based on MIC breakpoints. MIC breakpoints evolve over time based on new information; between 2010 and 2012 the CLSI lowered carbapenem breakpoints for Enterobacterales and Pseudomonas aeruginosa, and these were subsequently adopted by the US Food and Drug Administration. Carbapenems are important therapeutic options for these difficult-to-treat pathogens, so understanding resistance rates is critically important. However, laboratories can be slow to adopt updated breakpoints. We used MIC data to evaluate whether reports received by hospitals for carbapenem susceptibility were consistent with updated CLSI breakpoints. Although overall susceptibility rates were similar between hospital reports and susceptibility based on updated CLSI criteria, the percentages of carbapenem-resistant isolates were significantly underreported by hospital reports. Delayed adoption of MIC breakpoints may impact epidemiological understanding of resistance and contribute to the spread of resistant pathogens.
Topics: Anti-Bacterial Agents; Carbapenems; Laboratories, Clinical; Microbial Sensitivity Tests; Pseudomonas aeruginosa
PubMed: 35638777
DOI: 10.1128/spectrum.01158-22 -
Antibiotics (Basel, Switzerland) Apr 2022The objective of this study was to determine the presence and persistence of antimicrobial-resistant enterobacteria and their clonal distribution in hospital wastewater....
The objective of this study was to determine the presence and persistence of antimicrobial-resistant enterobacteria and their clonal distribution in hospital wastewater. A descriptive cross-sectional study was carried out in wastewater from two Mexico City tertiary level hospitals. In February and March of 2020, eight wastewater samples were collected and 26 isolates of enterobacteria were recovered, 19 (73.1%) isolates were identified as , 5 (19.2%) as spp. and 2 (7.7%) as spp. Antimicrobial susceptibility profiles were performed using the VITEK 2 automated system and bacterial identification was performed by the Matrix-Assisted Laser Desorption/Ionization-Time of Flight mass spectrometry (MALDI-TOF MS). ESBL genes were detected by polymerase chain reaction (PCR) and clonal distributions of isolates were determined by pulsed-field gel electrophoresis (PFGE). susceptibility to different classes of antimicrobials was analyzed and resistance was mainly detected as ESBLs and fluoroquinolones. One strain was resistant to doripenem, ertapenem, imipenem and meropenem. The analysis by PCR showed the presence of specific β-lactamases resistance genes (, ). The PFGE separated the isolates into 19 different patterns (A-R). PFGE results of spp. showed the presence of a majority clone A. Surveillance of antimicrobial resistance through hospital wastewater is an important tool for early detection of clonal clusters of clinically important bacteria with potential for dissemination.
PubMed: 35625245
DOI: 10.3390/antibiotics11050601 -
BMC Infectious Diseases May 2022Carbapenem-resistant Acinetobacter baumannii (CRAB) and carbapenem-resistant Pseudomonas aeruginosa (CRPA) are a growing threat. The objective of this study was to...
BACKGROUND
Carbapenem-resistant Acinetobacter baumannii (CRAB) and carbapenem-resistant Pseudomonas aeruginosa (CRPA) are a growing threat. The objective of this study was to describe CRAB and CRPA epidemiology and identify factors associated with mortality and length of stay (LOS) post-culture.
METHODS
This was a national retrospective cohort study of Veterans with CRAB or CRPA positive cultures from 2013 to 2018, conducted at Hines Veterans Affairs Hospital. Carbapenem resistance was defined as non-susceptibility to imipenem, meropenem and/or doripenem. Multivariable cluster adjusted regression models were fit to assess the association of post-culture LOS among inpatient and long-term care (LTC) and to identify factors associated with 90-day and 365-day mortality after positive CRAB and CRPA cultures.
RESULTS
CRAB and CRPA were identified in 1,048 and 8,204 unique patients respectively, with 90-day mortality rates of 30.3% and 24.5% and inpatient post-LOS of 26 and 27 days. Positive blood cultures were associated with an increased odds of 90-day mortality compared to urine cultures in patients with CRAB (OR 6.98, 95% CI 3.55-13.73) and CRPA (OR 2.82, 95% CI 2.04-3.90). In patients with CRAB and CRPA blood cultures, higher Charlson score was associated with increased odds of 90-day mortality. In CRAB and CRPA, among patients from inpatient care settings, blood cultures were associated with a decreased LOS compared to urine cultures.
CONCLUSIONS
Positive blood cultures and more comorbidities were associated with higher odds for mortality in patients with CRAB and CRPA. Recognizing these factors would encourage clinicians to treat these patients in a timely manner to improve outcomes of patients infected with these organisms.
Topics: Acinetobacter baumannii; Anti-Bacterial Agents; Carbapenems; Humans; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Retrospective Studies
PubMed: 35610601
DOI: 10.1186/s12879-022-07436-w -
PloS One 2022Carbapenem-resistant Escherichia coli has emerged as a major public health issue across the world. This study was aimed to determine the virulence content and...
Carbapenem-resistant Escherichia coli has emerged as a major public health issue across the world. This study was aimed to determine the virulence content and phylogenetic groups of carbapenemase-producing E. coli isolates in southwest Iran. One hundred and fifty-two non-duplicate E. coli isolates were collected from various clinical samples. Antibiotic susceptibility and minimum inhibitory concentrations (MIC) were determined according to the Clinical and Laboratory Standards Institute (CLSI) guidelines by Kirby-Bauer disc diffusion and agar dilution methods. Phenotypic screening of carbapenemase enzymes was performed by modified Hodge test (MHT). Detection of carbapenemase genes, phylogenetic groups, and virulence-associated genes were also performed by the PCR assay. The highest and lowest resistance rates were observed against mezlocillin (70.4%) and doripenem (13.1%), respectively. Out of 28 isolates that were resistant to carbapenem antibiotics, 12 (7.9%) strains were phenotypically carbapenemase producers. The blaOXA-48 was the predominant carbapenemase gene, detected in 58.3% of isolates, followed by blaIMP (41.7%) and blaNDM (8.3%). None of the isolates harbored blaVIM and blaKPC genes. Among the twelve carbapenemase-producing strains, urinary isolates were mostly classified into B2 (41.7%) and D (25%) phylogenetic groups, while other clinical isolates belonged to B1 (25%) and A (8.3%) groups. The frequency of virulence-associated genes was also investigated in all isolates and ranged from 6.6% for hly to 75% for fimA. The emergence of carbapenemase-producing strains is a growing concern to public health. Therefore, the proper implementation of monitoring programs is crucial for limiting their dissemination.
Topics: Anti-Bacterial Agents; Bacterial Proteins; Carbapenem-Resistant Enterobacteriaceae; Escherichia coli; Microbial Sensitivity Tests; Phylogeny; Virulence; beta-Lactamases
PubMed: 35536848
DOI: 10.1371/journal.pone.0266787 -
Frontiers in Pediatrics 2022The antimicrobial therapy of sepsis and septic shock should be individualized based on pharmacokinetic/pharmacodynamic (PK/PD) parameters to deliver effective and timely... (Review)
Review
The antimicrobial therapy of sepsis and septic shock should be individualized based on pharmacokinetic/pharmacodynamic (PK/PD) parameters to deliver effective and timely treatment of life-threatening infections. We conducted a literature scoping review to identify therapeutic targets of beta-lactam antibiotics in septic pediatric patients and the strategies that have been applied to overcome sepsis-related altered pharmacokinetics and increase target attainment against susceptible pathogens. A systematic search was conducted in the MEDLINE, EMBASE and Web of Science databases to select studies conducted since 2010 with therapeutic monitoring data of beta-lactams in septic children. Last searches were performed on 02 September 2021. Two independent authors selected the studies and extracted the data. A narrative and qualitative approach was used to summarize the findings. Out of the 118 identified articles, 21 met the eligibility criteria. Population pharmacokinetic modeling was performed in 12 studies, while nine studies reported data from bedside monitoring of beta-lactams. Most studies were conducted in the United States of America ( = 9) and France ( = 5) and reported PK/PD data of amoxicillin, ampicillin, azlocillin, aztreonam, cefazolin, cefepime, cefotaxime, ceftaroline, ceftazidime, doripenem, meropenem and piperacillin/tazobactam. Therapeutic targets ranged from to 40% T> MIC to 100% T> 6 × MIC. Prolonging the infusion time and frequency were most described strategies to increase target attainment. Monitoring beta-lactam serum concentrations in clinical practice may potentially maximize therapeutic target attainment. Further studies are required to define the therapeutic target associated with the best clinical outcomes.
PubMed: 35359889
DOI: 10.3389/fped.2022.777854 -
Antibiotics (Basel, Switzerland) Feb 2022We investigated the in vitro efficacy of combinations of carbapenems with clindamycin (CLDM) and minocycline (MINO) against Bacteroides fragilis and Peptostreptococcus...
We investigated the in vitro efficacy of combinations of carbapenems with clindamycin (CLDM) and minocycline (MINO) against Bacteroides fragilis and Peptostreptococcus species. We selected the carbapenems imipenem, meropenem, panipenem, doripenem, and biapenem. To evaluate the antibiotic efficacy of these combination regimens, the fractional inhibitory concentration index (FICI) was calculated against clinical isolates. Consequently, combination regimens of each carbapenem with CLDM or MINO showed synergistic or additive effects against 83.3−100.0% and no antagonistic effects against P. anaerobius isolates. However, against the B. fragilis group (B. fragilis, B. thetaiotaomicron, and Parabacteroides distasonis), although the combination with other carbapenems and CLDM or MINO did not show remarkable synergistic effects, the combination regimen of IPM with CLDM or MINO indicated mainly additive antibiotic efficacies (FICIs: >0.5 to ≤1.0) to B. fragilis groups. Then, antagonistic effects were admitted in only 5.6% of B. fragilis groups. The effectiveness of antibiotic combination therapy against pathogenic anaerobes has remained unclear. Then, our results can provide new insights to explore the effective combination regimens against multidrug-resistant anaerobic bacteria as empirical and definitive therapies, while this study used only carbapenem susceptible isolates. Hence, further studies are needed to use highly antibiotic-resistant anaerobic isolates to carbapenems.
PubMed: 35326756
DOI: 10.3390/antibiotics11030292