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The Journal of Antibiotics Dec 2022Klebsiella pneumoniae is an opportunistic pathogen causing nosocomial and community-acquired infections. Klebsiella has developed resistance against antimicrobials...
Klebsiella pneumoniae is an opportunistic pathogen causing nosocomial and community-acquired infections. Klebsiella has developed resistance against antimicrobials including the last resort class; carbapenem. Currently, treatment options for carbapenem-resistant-Klebsiella (CRK) are very limited. This study aims to restore carbapenem effectiveness against CRK using celastrol and thymol. Clinical Klebsiella isolates were identified using biochemical and molecular methods. Antimicrobial susceptibility was determined using disk-diffusion method. Carbapenemase-production was tested phenotypically and genotypically. Celastrol and thymol-MICs were determined and the carbapenemase-inhibitory effect of sub-MICs was investigated. Among 85 clinical Klebsiella isolates, 72 were multi-drug-resistant and 43 were meropenem-resistant. Phenotypically, 39 isolates were carbapenemase-producer. Genotypically, bla was detected in 35 isolates, bla in 17 isolates, bla in 18 isolates, and bla was detected only in 6 isolates. Celastrol showed significant inhibitory effect against carbapenemase-hydrolytic activity. Meropenem-MIC did not decrease in presence of celastrol, only 2-fold decrease was observed with thymol, while 4-64 fold decrease was observed when meropenem was combined with both celastrol and thymol. Furthermore, thymol increased CRK cell wall-permeability. Molecular docking revealed that celastrol is superior to thymol for binding to KPC and VIM-carbapenemase. Our study showed that celastrol is a promising inhibitor of multiple carbapenemases. While meropenem-MIC were not affected by celastrol alone and decreased by only 2-folds with thymol, it decreased by 4-64 folds in presence of both celastrol and thymol. Thymol increases the permeability of CRK-envelope to celastrol. The triple combination (meropenem/celastrol/thymol) could be useful for developing more safe and effective analogues to restore the activity of meropenem and other β-lactams.
Topics: Humans; Klebsiella pneumoniae; Meropenem; Thymol; Molecular Docking Simulation; Anti-Bacterial Agents; beta-Lactamases; Carbapenem-Resistant Enterobacteriaceae; Carbapenems; Microbial Sensitivity Tests; Bacterial Proteins; Klebsiella Infections
PubMed: 36167781
DOI: 10.1038/s41429-022-00566-y -
Medicine Jul 2023This study aimed to investigate the clinical characteristics, management and prognosis of Bacillus cereus sepsis in premature neonates. The clinical information of 8...
This study aimed to investigate the clinical characteristics, management and prognosis of Bacillus cereus sepsis in premature neonates. The clinical information of 8 premature neonates with B cereus sepsis who were treated in Shanghai Children Hospital from January 2015 to December 2019 was retrospectively collected from the medical records and analyzed. The neurodevelopment related conditions were collected at follow up visits at corrected age of 6 months and 12 months. Five patients developed meningitis, and cerebral magnetic resonance image showed abnormal in 5 patients. After treatment with meropenem and vancomycin, 1 patient died, and 7 patients survived and were smoothly discharged. At follow up visits, 1 patient was diagnosed with hydrocephalus and showed severely delayed neurodevelopment, 2 patients had mild delayed neurodevelopment, and the neurodevelopment was basically normal in remaining 4 patients. B cereus infection can cause severe complications of central nervous system, and affect neurodevelopmental outcome. Antibiotic treatment with meropenem and vancomycin is proven to be effective. Refreshing the central catheters is helpful for the prevention of B cereus sepsis and cerebral magnetic resonance image may be employed for the prognosis assessment.
Topics: Infant, Newborn; Child; Humans; Infant; Vancomycin; Bacillus cereus; Meropenem; Retrospective Studies; China; Sepsis; Prognosis; Infant, Newborn, Diseases
PubMed: 37443518
DOI: 10.1097/MD.0000000000034261 -
Microbial Drug Resistance (Larchmont,... Aug 2023We examined the susceptibility of meropenem-nonsusceptible Enterobacterales, , and complex isolates from five consecutive annual SIDERO-WT surveillance studies...
We examined the susceptibility of meropenem-nonsusceptible Enterobacterales, , and complex isolates from five consecutive annual SIDERO-WT surveillance studies (2014-2019) to cefiderocol and comparator agents in the context of their carbapenemase carriage. 1,003 Enterobacterales, 1,758 , and 2,809 complex isolates from North America and Europe that were meropenem nonsusceptible (CLSI M100, 2022) were molecularly characterized for β-lactamase content by PCR followed by Sanger sequencing or by whole genome sequencing. Among Enterobacterales, 91.5% of metallo-β-lactamase (MBL)-producing, 98.4% of KPC-producing, 97.3% of OXA-48 group-producing, and 98.7% of carbapenemase-negative, meropenem-nonsusceptible isolates were cefiderocol susceptible (MIC ≤4 mg/L). Among , 100% of MBL-producing, 100% of GES carbapenemase-producing, and 99.8% of carbapenemase-negative, meropenem-nonsusceptible isolates were cefiderocol susceptible (MIC ≤4 mg/L). Among complex, 60.0% of MBL-producing, 95.6% of OXA-23 group-producing, 89.5% of OXA-24 group-producing, 100% of OXA-58 group-producing, and 95.5% of carbapenemase-negative, meropenem-nonsusceptible isolates were cefiderocol susceptible (MIC ≤4 mg/L). Cefiderocol was inactive against complex isolates carrying a PER or VEB β-lactamase ( = 103; 15.5% susceptible). Ceftazidime-avibactam and ceftolozane-tazobactam were inactive against MBL-carrying and complex isolates; ceftolozane-tazobactam was also inactive against serine carbapenemase-carrying Enterobacterales and . In summary, cefiderocol was highly active against Gram-negative isolates carrying MBLs and serine carbapenemases, as well as carbapenemase-negative, meropenem-nonsusceptible isolates.
Topics: Meropenem; Anti-Bacterial Agents; Microbial Sensitivity Tests; Gram-Negative Bacteria; Tazobactam; beta-Lactamases; Pseudomonas aeruginosa; Azabicyclo Compounds; Cefiderocol
PubMed: 37253158
DOI: 10.1089/mdr.2022.0279 -
Antimicrobial Agents and Chemotherapy Oct 2022Xeruborbactam (formerly QPX7728) is a cyclic boronate inhibitor of numerous serine and metallo-beta-lactamases. At concentrations generally higher than those required...
Xeruborbactam (formerly QPX7728) is a cyclic boronate inhibitor of numerous serine and metallo-beta-lactamases. At concentrations generally higher than those required for beta-lactamase inhibition, xeruborbactam has direct antibacterial activity against some Gram-negative bacteria, with MIC/MIC values of 16/32 μg/mL and 16/64 μg/mL against carbapenem-resistant and carbapenem-resistant Acinetobacter baumannii, respectively (the MIC/MIC values against Pseudomonas aeruginosa are >64 μg/mL). In Klebsiella pneumoniae, inactivation of OmpK36 alone or in combination with OmpK35 resulted in 2- to 4-fold increases in the xeruborbactam MIC. In A. baumannii and P. aeruginosa, AdeIJK and MexAB-OprM, respectively, affected xeruborbactam's antibacterial potency (the MICs were 4- to 16-fold higher in efflux-proficient strains). In Escherichia coli and K. pneumoniae, the 50% inhibitory concentrations (ICs) of xeruborbactam's binding to penicillin-binding proteins (PBPs) PBP1a/PBP1b, PBP2, and PBP3 were in the 40 to 70 μM range; in A. baumannii, xeruborbactam bound to PBP1a, PBP2, and PBP3 with ICs of 1.4 μM, 23 μM, and 140 μM, respectively. Treating K. pneumoniae and P. aeruginosa with xeruborbactam at 1× and 2× MIC resulted in changes of cellular morphology similar to those observed with meropenem; the morphological changes observed after treatment of A. baumannii were consistent with inhibition of multiple PBPs but were unique to xeruborbactam compared to the results for control beta-lactams. No single-step xeruborbactam resistance mutants were obtained after selection at 4× MIC of xeruborbactam using wild-type strains of E. coli, K. pneumoniae, and A. baumannii; mutations selected at 2× MIC in K. pneumoniae did not affect antibiotic potentiation by xeruborbactam through beta-lactamase inhibition. Consistent with inhibition of PBPs, xeruborbactam enhanced the potencies of beta-lactam antibiotics even against strains that lacked beta-lactamase. In a large panel of KPC-producing clinical isolates, the MIC values of meropenem tested with xeruborbactam (8 μg/mL) were at least 4-fold lower than those in combination with vaborbactam at 64 μg/mL, the concentration of vaborbactam that is associated with complete inhibition of KPC. The additional enhancement of the potency of beta-lactam antibiotics beyond beta-lactamase inhibition may contribute to the potentiation of beta-lactam antibiotics by xeruborbactam.
Topics: Meropenem; Penicillin-Binding Proteins; Escherichia coli; Anti-Bacterial Agents; beta-Lactamases; beta-Lactams; Microbial Sensitivity Tests; Klebsiella pneumoniae; Carbapenems; Monobactams; Pseudomonas aeruginosa; Serine
PubMed: 36102663
DOI: 10.1128/aac.00879-22 -
Clinical Microbiology and Infection :... Nov 2022New antibiotics have been developed to treat multidrug-resistant Enterobacterales. We evaluated the impact of the inoculum size on minimal inhibitory concentrations...
OBJECTIVES
New antibiotics have been developed to treat multidrug-resistant Enterobacterales. We evaluated the impact of the inoculum size on minimal inhibitory concentrations (MICs) of recently commercialized antibiotics.
METHODS
We focused on 40 clinical carbapenemase-producing Enterobacterales and evaluated the impact of the inoculum size on the MICs to cefiderocol and to new β-lactams/β-lactamase inhibitors (ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-relebactam, and meropenem-vaborbactam) at usual and high inocula (10 and 10 CFU/mL, respectively).
RESULTS
At usual inoculum, 15% were resistant to cefiderocol (n = 6), 30% to meropenem-vaborbactam (n = 12), 42.5% to ceftazidime-avibactam (n = 17), 55% to imipenem-relebactam (n = 22), and 90% to ceftolozane-tazobactam (n = 36). At higher inoculum, a switch from susceptible to resistant category was observed for 88% (n = 30/34; CI, 71.6-96.2), 75% (n = 3/4; CI, 21.9-98.7), 72% (n = 13/18; CI, 46.4-89.3), 50% (n = 14/28; CI, 31.1-68.9), and 8.7% (n = 2/23; CI, 1.5-29.5) isolates regarding cefiderocol, ceftolozane-tazobactam, imipenem-relebactam, meropenem-vaborbactam, and ceftazidime-avibactam, respectively.
DISCUSSION
Cefiderocol and meropenem-vaborbactam were the most efficient against carbapenemase-producing Enterobacterales at usual inoculum. When increasing inoculum to 10 CFU/mL, all of the molecules were impacted, particularly cefiderocol and imipenem-relebactam, while others, such as ceftazidime-avibactam, remain mildly affected. Our in vitro results deserved to be confirmed in vivo.
Topics: Humans; Anti-Bacterial Agents; Meropenem; beta-Lactamase Inhibitors; Carbapenems; Tazobactam; Imipenem; Cefiderocol
PubMed: 35777602
DOI: 10.1016/j.cmi.2022.06.018 -
Antimicrobial Agents and Chemotherapy Jun 2023Model-informed precision dosing (MIPD) maximizes the probability of successful dosing in patients undergoing hemodialysis. In these patients, area under the...
Model-informed precision dosing (MIPD) maximizes the probability of successful dosing in patients undergoing hemodialysis. In these patients, area under the concentration-time curve (AUC)-guided dosing is recommended for vancomycin. However, this model is yet to be developed. The purpose of this study was to address this issue. The overall mass transfer-area coefficient (KoA) was used for the estimation of vancomycin hemodialysis clearance. A population pharmacokinetic (popPK) model was developed, resulting in a fixed-effect parameter for nonhemodialysis clearance of 0.316 liters/h. This popPK model was externally evaluated, with a resulting mean absolute error of 13.4% and mean prediction error of -0.17%. KoA-predicted hemodialysis clearance was prospectively evaluated for vancomycin ( = 10) and meropenem ( = 10), with a correlation equation being obtained (slope of 1.099, intercept of 1.642; = 0.927, < 0.001). An experimental evaluation using an hemodialysis circuit validated the developed model of KoA-predicted hemodialysis clearance using vancomycin, meropenem, vitamin B, and inulin in 12 hemodialysis settings. This popPK model indicated a maximum dosing for vancomycin-a loading dose of 30 mg/kg, which achieves the target AUC for 24 h after first dose with a probability of 93.0%, ensured by a predialysis concentration of >15 μg/mL. Maintenance doses of 12 mg/kg after every hemodialysis session could achieve the required exposure, with a probability of 80.6%. In conclusion, this study demonstrated that KoA-predicted hemodialysis clearance may lead to an upgrade from conventional dosing to MIPD for vancomycin in patients undergoing hemodialysis.
Topics: Humans; Adult; Vancomycin; Anti-Bacterial Agents; Meropenem; Renal Dialysis; Probability
PubMed: 37195225
DOI: 10.1128/aac.00089-23 -
Antimicrobial Agents and Chemotherapy Aug 2023In 2021, Klebsiella pneumoniae sequence type 307 (ST307) strains causing pulmonary and bloodstream infections identified in a hospital in Rome, Italy, reached high...
In 2021, Klebsiella pneumoniae sequence type 307 (ST307) strains causing pulmonary and bloodstream infections identified in a hospital in Rome, Italy, reached high levels of resistance to ceftazidime-avibactam (CZA). One of these strains reached high levels of resistance to both CZA and carbapenems and carried two copies of and one copy of located on plasmid pKpQIL. The genomes and plasmids of CZA-resistant ST307 strains were analyzed to identify the molecular mechanisms leading to the evolution of resistance and compared with ST307 genomes at local and global levels. A complex pattern of multiple plasmids in rearranged configurations, coresident within the CZA-carbapenem-resistant K. pneumoniae strain, was observed. Characterization of these plasmids revealed recombination and segregation events explaining why K. pneumoniae isolates from the same patient had different antibiotic resistance profiles. This study illustrates the intense genetic plasticity occurring in ST307, one of the most worldwide-diffused K. pneumoniae high-risk clones.
Topics: Humans; Meropenem; Anti-Bacterial Agents; Klebsiella pneumoniae; Klebsiella Infections; Bacterial Proteins; beta-Lactamases; Ceftazidime; Azabicyclo Compounds; Plasmids; Carbapenems; Microbial Sensitivity Tests
PubMed: 37428086
DOI: 10.1128/aac.00368-23 -
Antimicrobial Agents and Chemotherapy Feb 2021is recognized as an urgent public health threat by the Centers for Disease Control and Prevention (CDC). Current treatment options are scarce, particularly against...
Minocycline Alone and in Combination with Polymyxin B, Meropenem, and Sulbactam against Carbapenem-Susceptible and -Resistant Acinetobacter baumannii in an Pharmacodynamic Model.
is recognized as an urgent public health threat by the Centers for Disease Control and Prevention (CDC). Current treatment options are scarce, particularly against carbapenem-resistant (CRAB). We simulated the impact of minocycline standard (200 mg load + 100 mg Q12h) and high (700 mg load + 350 mg Q12h) doses, polymyxin B (2.5 mg/kg Q12h), sulbactam (1 g Q6h and 9 g/24 h as continuous infusion), and meropenem (intermittent 1 or 2 g Q8h and 6 g/24 h as continuous infusion) alone or in combination against CRAB and non-CRAB isolates by simulating human therapeutic dosing regimens in a 72-h, pharmacodynamic (IVPD) model. There were no monotherapy regimens that demonstrated bactericidal activity against the tested non-CRAB and CRAB strains. Resistance development was common in monotherapy regimens. Against the CRAB isolate, the triple combination of high-dose minocycline (AUC/MIC 21.2), polymyxin B (AUC/MIC 15.6), and continuous-infusion sulbactam (67% ) was the most consistently active regimen. Against non-CRAB, the triple therapy regimen of high-dose minocycline (AUC/MIC 84.8) with continuous-infusion meropenem (100% ) and continuous-infusion sulbactam (83% ), as well as the double therapy of high-dose minocycline (AUC/MIC 84.8) with continuous-infusion meropenem (100% ), resulted in persistently bactericidal activity. In conclusion, triple therapy with high-dose minocycline, continuous-infusion sulbactam, and polymyxin B produced the most significant kill against the carbapenem-resistant , with no regrowth and minimal resistance development.
Topics: Acinetobacter Infections; Acinetobacter baumannii; Anti-Bacterial Agents; Carbapenems; Drug Synergism; Humans; Meropenem; Microbial Sensitivity Tests; Minocycline; Polymyxin B; Sulbactam
PubMed: 33318006
DOI: 10.1128/AAC.01680-20 -
Antimicrobial Agents and Chemotherapy Nov 2023β-Lactam antibiotics are among the most frequently prescribed therapeutic agents. A common mechanism of resistance toward β-lactam antibiotics is the production of...
β-Lactam antibiotics are among the most frequently prescribed therapeutic agents. A common mechanism of resistance toward β-lactam antibiotics is the production of β-lactamases. These enzymes are capable of hydrolyzing the β-lactam bond, rendering the drug inactive. Among the four described classes, the metallo- β-lactamases (MBLs, class B) employ one or two zinc ions in the active site for catalysis. One of the three most clinically relevant MBLs is New Delhi Metallo- β-Lactamase (NDM-1). The current study sought to investigate the protein evolution of NDM-1 β-lactamase using error-prone polymerase chain reaction. Evaluation revealed that variants were not found to confer higher levels of resistance toward meropenem based on amino acid substitutions. Thus, we postulate that increases in transcription or changes in zinc transport may be clinically more relevant to meropenem resistance than amino acid substitutions.
Topics: Meropenem; beta-Lactamases; beta-Lactams; Zinc; Catalytic Domain; Anti-Bacterial Agents; beta-Lactamase Inhibitors
PubMed: 37874296
DOI: 10.1128/aac.00714-23 -
Antimicrobial Agents and Chemotherapy May 2023Dissemination of hypervirulent and carbapenem-resistant Klebsiella pneumoniae (CRKP) has been reported worldwide, posing a serious threat to antimicrobial therapy and...
Dissemination of hypervirulent and carbapenem-resistant Klebsiella pneumoniae (CRKP) has been reported worldwide, posing a serious threat to antimicrobial therapy and public health. Outer membrane vesicles (OMVs) act as vectors for the horizontal transfer of virulence and resistance genes. However, K. pneumoniae OMVs that transfer carbapenem resistance genes into hypervirulent K. pneumoniae (hvKP) have been insufficiently investigated. Therefore, this study investigates the transmission of the gene encoding resistance via OMVs released from CRKP and the potential mechanism responsible for the carbapenem-resistant hypervirulent K. pneumoniae (CR-hvKP) emergence. OMVs were isolated via ultracentrifugation from CRKP with or without meropenem selective pressure. OMVs were then used to transform classical K. pneumoniae (ckp) ATCC 10031, extended-spectrum β-lactamase (ESBL)-producing K. pneumoniae ATCC 700603, and hvKP NTUH-K2044. Our results showed that meropenem treatment resulted in changes in the number and diameter of OMVs secreted by CRKP. OMVs derived from CRKP mediated the transfer of to ckp and hvKP, thereby increasing the carbapenem MIC of transformants. Further experiments confirmed that NTUH-K2044 transformants exhibited hypervirulence. Our study demonstrates, for the first time, that OMVs derived from CRKP can carry and deliver resistance genes to other K. pneumoniae strains, even hvKP. The transfer of carbapenem genes into hypervirulent strains may promote the emergence and dissemination of CR-hvKP. This study elucidates a new mechanism underlying the formation of CR-hvKP.
Topics: Humans; Klebsiella pneumoniae; Meropenem; Klebsiella Infections; Carbapenems; Anti-Bacterial Agents; Carbapenem-Resistant Enterobacteriaceae
PubMed: 37052502
DOI: 10.1128/aac.01444-22