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Pathogens (Basel, Switzerland) Jul 2022is ubiquitous in aquatic habitats and can cause life-threatening septicaemia in humans. However, limited data are available on their antimicrobial susceptibility...
is ubiquitous in aquatic habitats and can cause life-threatening septicaemia in humans. However, limited data are available on their antimicrobial susceptibility testing (AST) profiles. Hence, we aimed to examine their AST patterns using clinical ( = 94) and non-clinical ( = 23) isolates with dehydrated MicroScan microdilution. Carbapenem resistant isolates were further screened for genes related to carbapenem resistance using molecular assay. The isolates exhibited resistance to imipenem (76.9%), doripenem (62.4%), meropenem (41.9%), trimethoprim/sulfamethoxazole (11.1%), cefotaxime (8.5%), ceftazidime (6%), cefepime (1.7%) and aztreonam (0.9%), whereas all isolates were susceptible to amikacin. Clinical isolates showed significant association with resistance to doripenem, imipenem and meropenem compared to non-clinical isolates. These were detected in clinical isolates with resistance phenotypes: doripenem (67.2%, 45/67), imipenem (65.9%, 54/82) and meropenem (65.2%, 30/46). Our findings showed that the MicroScan microdilution method is suitable for the detection of carbapenem resistance in both clinical (48.9-87.2%) and non-clinical (4.3-13.0%) isolates. This study revealed that isolates had relatively high carbapenem resistance, which may lead to potential treatment failure. Continued monitoring of aquatic sources with a larger sample size should be carried out to provide further insights.
PubMed: 35894056
DOI: 10.3390/pathogens11080833 -
Journal of Clinical Medicine Jul 2022Clinically, doripenem therapy for nosocomial pneumonia remains a serious concern. The purpose of this meta-analysis was to explore the efficacy and the safety of... (Review)
Review
INTRODUCTION
Clinically, doripenem therapy for nosocomial pneumonia remains a serious concern. The purpose of this meta-analysis was to explore the efficacy and the safety of doripenem therapy for nosocomial pneumonia in comparison with other antimicrobial agents.
METHODS
Studies were eligible for inclusion only if they directly compared the clinical effectiveness of doripenem and other antimicrobial agent therapies for nosocomial pneumonia in adult patients between 1 January 2000 and 30 April 2022. All studies were included if they reported one or more of the following outcomes: clinical cure rate, microbiological cure rate, all-cause mortality, and adverse events.
RESULTS
Six randomized controlled trials and three retrospective studies were included in the meta-analysis. There were 952 patients in the doripenem group and 1183 patients in the comparator group. The comparator antimicrobial agents included imipenem/cilastatin, meropenem, and piperacillin/tazobactam. Seven studies had a high risk of bias. Doripenem therapy for nosocomial pneumonia had a microbiological cure rate, a clinical cure rate, an all-cause mortality, and adverse events similar to those of comparators.
CONCLUSIONS
The efficacy and the safety of doripenem therapy for nosocomial pneumonia were comparable with those of comparators. Randomized controlled trials are needed to confirm the role of doripenem in nosocomial pneumonia therapy.
PubMed: 35887777
DOI: 10.3390/jcm11144014 -
Antibiotics (Basel, Switzerland) Jul 2022The aim of this study was to investigate the pharmacokinetics (PK) of doripenem in healthy Chinese subjects and evaluate the optimal dosage regimens of doripenem. A...
The aim of this study was to investigate the pharmacokinetics (PK) of doripenem in healthy Chinese subjects and evaluate the optimal dosage regimens of doripenem. A randomized, single-dose, three-period, self-crossover controlled extended-infusion clinical trial was conducted with 12 healthy Chinese subjects. Plasma and urine samples were collected to determine doripenem concentrations. Non-compartmental and population PK analysis were performed to characterize the PK of doripenem. The Monte Carlo simulation was employed to optimize dosing regimens based on the probability of target attainment of doripenem against pathogens with different minimum inhibitory concentrations (MIC). All 12 healthy Chinese subjects completed the study, and the doripenem was well tolerated. The study showed linearity relationships in the peak plasma concentration and the area under the concentration-time curve after intravenous infusion of doripenem from 0.25 g to 1.0 g. The cumulative urinary recovery rate of doripenem was 68.1-72.0% within 24 h. PPK modeling showed a two-compartmental model, with first-order elimination presenting the best fit for doripenem PK. Monte Carlo simulation results showed that 1.0 g q12h or 0.5 g q8h was an optimal regimen for pathogens susceptible to doripenem (MIC ≤ 1 mg/L); while high dose and extended infusion (1 g, q8h, 4 h infusion) was proposed for unsusceptible pathogens (2 ≤ MIC ≤ 8 mg/L). In the dose range of 0.25 to 1.0 g, doripenem showed linear pharmacokinetics. Doripenem at 1.0 g with a prolonged infusion time of 4 h was predicted to be effective against pathogens with MICs as high as 8 mg/L.
PubMed: 35884212
DOI: 10.3390/antibiotics11070958 -
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 -
Journal of Applied Microbiology Sep 2022This study was performed to identify the potential for repurposing auranofin as an antibiotic adjuvant against carbapenemase-producing Acinetobacter baumannii.
AIMS
This study was performed to identify the potential for repurposing auranofin as an antibiotic adjuvant against carbapenemase-producing Acinetobacter baumannii.
METHODS AND RESULTS
The clinically isolated A. baumannii strains used in this study were all resistant to carbapenems and harboured the bla gene. The synergistic effect of auranofin and doripenem against carbapenemase-producing A. baumannii was confirmed through checkerboard and growth kinetic analyses. This study also demonstrated the inhibitory effects of auranofin against A. baumannii biofilms. The anti-biofilm effects of auranofin were visualized by confocal laser scanning microscopy (CLSM). Furthermore, auranofin inhibited motility, one of the virulence factors. Additionally, the changes in the expression of carbapenemase-, biofilm- and efflux pump-related genes induced by auranofin were confirmed via quantitative polymerase chain reaction (qPCR).
CONCLUSIONS
Our results demonstrated that auranofin has an antibacterial effect with doripenem and an inhibitory effect on several factors related to carbapenem resistance.
SIGNIFICANCE AND IMPACT OF THE STUDY
This study suggests that auranofin is a promising antibiotic adjuvant that can be used to prevent antibiotic resistance in carbapenem-resistant A. baumannii.
Topics: Acinetobacter Infections; Acinetobacter baumannii; Anti-Bacterial Agents; Auranofin; Bacterial Proteins; Carbapenems; Doripenem; Drug Resistance, Multiple, Bacterial; Humans; Microbial Sensitivity Tests; beta-Lactamases
PubMed: 35633297
DOI: 10.1111/jam.15644 -
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