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International Journal of Antimicrobial... Apr 2023To evaluate the in-vitro activity of ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, imipenem-relebactam and comparator agents against contemporary...
OBJECTIVES
To evaluate the in-vitro activity of ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, imipenem-relebactam and comparator agents against contemporary Pseudomonas aeruginosa isolates from US hospitals.
METHODS
In total, 3184 isolates were collected consecutively from 71 US medical centres in 2020-2021, and susceptibility tested by reference broth microdilution. Clinical Laboratory Standard Institute breakpoints were applied.
RESULTS
Ceftazidime-avibactam [97.0% susceptible (S)], ceftolozane-tazobactam (98.0%S), imipenem-relebactam (97.3%S) and tobramycin (96.4%S) were the most active agents against the aggregate P. aeruginosa isolate collection, and retained good activity against piperacillin-tazobactam-non-susceptible, meropenem-non-susceptible and multi-drug-resistant (MDR) isolates. All other antimicrobials tested showed limited activity against piperacillin-tazobactam-non-susceptible, meropenem-non-susceptible and MDR isolates. The most common infections were pneumonia (45.9%), skin and skin structure infections (19.0%), urinary tract infections (17.0%) and bloodstream infections (11.7%); ceftazidime-avibactam, ceftolozane-tazobactam and imipenem-relebactam showed consistent activity against isolates from these infection types. Susceptibility to piperacillin-tazobactam and meropenem was lower among isolates from pneumonia compared with other infection types.
CONCLUSIONS
Ceftazidime-avibactam, ceftolozane-tazobactam and imipenem-relebactam were highly active, and exhibited similar coverage against a large contemporary collection of P. aeruginosa isolates from US hospitals. Cross-resistance among the newer β-lactams/β-lactam inhibitors (BL/BLIs) varied markedly; ≥72.1% of isolates resistant to one of the three newer BL/BLIs approved for P. aeruginosa treatment remained susceptible to at least one of the other two BL/BLIs, indicating that all three should be tested in the clinical laboratory. These three BL/BLIs represent valuable therapeutic options for P. aeruginosa infection.
Topics: Humans; beta-Lactamase Inhibitors; Meropenem; Pseudomonas aeruginosa; Lactams; Cephalosporins; Anti-Bacterial Agents; Tazobactam; Ceftazidime; Azabicyclo Compounds; Piperacillin, Tazobactam Drug Combination; Drug Combinations; Imipenem; Pneumonia; Hospitals; Microbial Sensitivity Tests; Pseudomonas Infections
PubMed: 36738849
DOI: 10.1016/j.ijantimicag.2023.106744 -
BMC Microbiology Dec 2022Acinetobacter baumannii (A. baumannii) is one of the members of ESKAPE bacteria which is considered multidrug resistant globally. The objective of this study is to...
Acinetobacter baumannii (A. baumannii) is one of the members of ESKAPE bacteria which is considered multidrug resistant globally. The objective of this study is to determine the protein docking of different antibiotic resistance gene (ARGs) in A. baumannii. In silico analysis of antibiotic resistance genes against carbapenem are the blaOXA-51, blaOXA-23, blaOXA-58, blaOXA-24, blaOXA-143, NMD-1 and IMP-1 in A. baumannii. The doripenem, imipenem and meropenem were docked to blaOXA-51 and blaOXA-23 using PyRx. The top docking energy was -5.5 kcal/mol by imipenem and doripenem and meropenem showed a binding score of -5. 2 kcal/mol each and blaOXA-23 energy was -4.3 kcal/mol by imipenem and meropenem showed a binding score of -2.3 kcal/mol, while doripenem showed the binding score of -3.4 kcal/mol. Similarly, doripenem imipenem and meropenem were docked to blaOXA-58, IMP-1, Rec A and blaOXA-143, with docking energy was -8.8 kcal/mol by doripenem and meropenem each while imipenem showed a binding score of -4.2 kcal/mol and with IMP-1 demonstrated their binding energies. was -5.7 kcal/mol by meropenem and doripenem showed a binding score of -5.3 kcal/mol, while imipenem showed a binding score of -4.5 kcal/mol. And docking energy was -4.9 kcal/mol by imipenem and meropenem showed binding energy of -3.6 kcal/mol each while doripenem showed a binding score of -3.9 kcal/mol in RecA and with blaOXA-143 docking energy was -3.0 kcal/mol by imipenem and meropenem showed a binding score of -1.9 kcal/mol, while doripenem showed the binding score of -2.5 kcal/mol respectively. Doripenem, imipenem, and meropenem docking findings with blaOXA-24 confirmed their binding energies. Doripenem had the highest docking energy of -5.5 kcal/mol, meropenem had a binding score of -4.0 kcal/mol, and imipenem had a binding score of -3.9 kcal/mol. PyRx was used to dock the doripenem, imipenem, and meropenem to NMD-1. Docking energies for doripenem were all - 4.0 kcal/mol, whereas meropenem had docking energy of -3.3 kcal/mol and imipenem was -1.50 kcal/mol. To the best of our knowledge the underlying mechanism of phenotypic with genotypic resistance molecular docking regarding carbapenem resistance A. baumannii is unclear. Our molecular docking finds the possible protein targeting mechanism for carbapenem-resistant A.baumannii.
Topics: Acinetobacter baumannii; Anti-Bacterial Agents; Carbapenems; Doripenem; Imipenem; Meropenem; Molecular Docking Simulation
PubMed: 36463105
DOI: 10.1186/s12866-022-02706-8 -
Scientific Reports Nov 2022Understanding the response of bacteria to environmental stress is hampered by the relative insensitivity of methods to detect growth. This means studies of antibiotic...
Understanding the response of bacteria to environmental stress is hampered by the relative insensitivity of methods to detect growth. This means studies of antibiotic resistance and other physiological methods often take 24 h or longer. We developed and tested a scattered light and detection system (SLIC) to address this challenge, establishing the limit of detection, and time to positive detection of the growth of small inocula. We compared the light-scattering of bacteria grown in varying high and low nutrient liquid medium and the growth dynamics of two closely related organisms. Scattering data was modelled using Gompertz and Broken Stick equations. Bacteria were also exposed meropenem, gentamicin and cefoxitin at a range of concentrations and light scattering of the liquid culture was captured in real-time. We established the limit of detection for SLIC to be between 10 and 100 cfu mL in a volume of 1-2 mL. Quantitative measurement of the different nutrient effects on bacteria were obtained in less than four hours and it was possible to distinguish differences in the growth dynamics of Klebsiella pneumoniae 1705 possessing the Bla betalactamase vs. strain 1706 very rapidly. There was a dose dependent difference in the speed of action of each antibiotic tested at supra-MIC concentrations. The lethal effect of gentamicin and lytic effect of meropenem, and slow bactericidal effect of cefoxitin were demonstrated in real time. Significantly, strains that were sensitive to antibiotics could be identified in seconds. This research demonstrates the critical importance of improving the sensitivity of bacterial detection. This results in more rapid assessment of susceptibility and the ability to capture a wealth of data on the growth dynamics of bacteria. The rapid rate at which killing occurs at supra-MIC concentrations, an important finding that needs to be incorporated into pharmacokinetic and pharmacodynamic models. Importantly, enhanced sensitivity of bacterial detection opens the possibility of susceptibility results being reportable clinically in a few minutes, as we have demonstrated.
Topics: Anti-Bacterial Agents; Meropenem; Cefoxitin; Klebsiella pneumoniae; Gentamicins; Microbial Sensitivity Tests
PubMed: 36371444
DOI: 10.1038/s41598-022-22671-6 -
BMJ Case Reports Sep 2021Meropenem is a broad-spectrum carbapenem widely used to treat both Gram-positive and negative bacterial infections, including extended-spectrum beta-lactamase-producing...
Meropenem is a broad-spectrum carbapenem widely used to treat both Gram-positive and negative bacterial infections, including extended-spectrum beta-lactamase-producing microbes. We describe the occurrence of thrombocytopenia and hypersensitivity in a boy receiving intravenous meropenem for intra-abdominal sepsis secondary to perforated appendicitis. The patient developed a pruritic maculopapular rash with occasional petechiae, associated with severe thrombocytopenia, after 7 days of meropenem administration. Investigations for other causes of thrombocytopenia, including possible line sepsis, were unfruitful, and the thrombocytopenia did not resolve until cessation of meropenem. Drug-induced reactions should be considered in children receiving meropenem who present with a rash and thrombocytopenia.
Topics: Anti-Bacterial Agents; Bacterial Infections; Child; Humans; Male; Meropenem; Thienamycins; Thrombocytopenia
PubMed: 34479885
DOI: 10.1136/bcr-2021-243443 -
Blood Purification 2023The optimal meropenem dosing regimens in critically ill patients receiving continuous renal replacement therapy (CRRT) based on pharmacokinetic and pharmacodynamic (PD)...
INTRODUCTION
The optimal meropenem dosing regimens in critically ill patients receiving continuous renal replacement therapy (CRRT) based on pharmacokinetic and pharmacodynamic (PD) concepts are not well established. This study aimed to (1) gather the available published pharmacokinetic studies conducted in septic patients receiving CRRT and (2) to define the optimal meropenem dosing regimens in these populations via Monte Carlo simulations.
METHODS
We used Medical Subject Headings "meropenem," "continuous renal replacement therapy," and "pharmacokinetics" or related terms to identify studies for systematic review. A one-compartment pharmacokinetic model was conducted to predict meropenem levels for the initial 48 h of therapy. The PD targets were 40% of free drug above a threshold of 1 times the minimum inhibitory concentration (MIC) (40% fT > MIC), 4 times the MIC (40% fT > 4MIC), and an additional target of free drug level above 1 times MIC 100% of the time (fT > MIC). The dose that achieved at least 90% of the probability of target attainment (PTA) was defined as an optimal dose.
RESULTS
Twenty-one articles were included for our systematic review. The necessary pharmacokinetic parameters such as volume of distribution and CRRT clearance were cited in 90.5 and 71.4% of articles, respectively. None of the published studies reported completed necessary parameters. A regimen of 750 mg q 8 h was found to be the optimal dose for pre-dilution continuous venovenous hemofiltration and continuous venovenous hemodialysis modality using two effluent rates (25 and 35 mL/kg/h) which achieved the PD target of 40% fT > 4MIC.
CONCLUSION
None of the published studies showed the necessary pharmacokinetic parameters. PD target significantly contributed to meropenem dosage regimens in these patients. Differing effluent rates and types of CRRT shared similar dosing regimens. Clinical validation of the recommendation is suggested.
Topics: Humans; Meropenem; Continuous Renal Replacement Therapy; Anti-Bacterial Agents; Monte Carlo Method; Critical Illness; Renal Replacement Therapy
PubMed: 37231811
DOI: 10.1159/000529694 -
Indian Journal of Pharmacology 2021Meropenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa are the two most common nosocomial pathogens causing ventilator-associated pneumonia. To combat...
BACKGROUND
Meropenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa are the two most common nosocomial pathogens causing ventilator-associated pneumonia. To combat this resistance, different combinations of antibiotics have been evaluated for their efficacy in laboratories as well as in clinical situations.
AIM
The aim of the study was to investigate the effect of combined colistin and meropenem against meropenem-resistant isolates of A. baumannii and P. aeruginosa by checkerboard method.
MATERIALS AND METHODS
Fifty meropenem-resistant isolates of A. baumannii (n = 25) and P. aeruginosa (n = 25) from endotracheal aspirates were studied. The MIC of colistin and meropenem was found using the microbroth dilution method. The fractional inhibitory concentration was calculated for the combination of antibiotics by checkerboard assay and the antibiotic interactions were assessed. Fisher's exact test was carried out for statistical comparison of categorical variables.
RESULTS
A synergistic effect between colistin and meropenem was observed in 18/25 (72%) and 6/25 (24%) isolates of Acinetobacter baumannnii and P. Aeruginosa, respectively, with fractional inhibitory concentration indices of ≤0.5. None of the tested isolates exhibited antagonism.
CONCLUSION
Our results showed that combinations of colistin and meropenem are associated with improvement in minimum inhibitory concentration and may be a promising strategy in treating meropenem-resistant A. baumannii respiratory tract infections.
Topics: Acinetobacter baumannii; Anti-Bacterial Agents; Colistin; Cross-Sectional Studies; Drug Combinations; Drug Resistance, Multiple, Bacterial; Drug Synergism; Humans; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa
PubMed: 34169905
DOI: 10.4103/ijp.ijp_1013_20 -
BMC Microbiology Oct 2023Hospital infections such as ventilator-associated pneumonia (VAP) due to multidrug-resistant Klebsiella pneumoniae (MDR-KP) strains have increased worldwide. In...
In Vitro antibiotic combinations of Colistin, Meropenem, Amikacin, and Amoxicillin/clavulanate against multidrug-resistant Klebsiella pneumonia isolated from patients with ventilator-associated pneumonia.
BACKGROUND
Hospital infections such as ventilator-associated pneumonia (VAP) due to multidrug-resistant Klebsiella pneumoniae (MDR-KP) strains have increased worldwide. In addition, biofilm production by these resistant isolates has confronted clinicians with higher treatment failure and infection recurrence. Given the paucity of new agents and limited data on combination therapy for MDR-KPs, the present study sought to evaluate the in vitro activity of several antibiotic combinations against planktonic and biofilm MDR-KPs isolated from patients with VAP.
RESULTS
All 10 carbapenem-resistant Klebsiella pneumoniae (CRKP) isolates demonstrated multidrug resistance against the tested antibiotics. At planktonic mode, combinations of colistin-meropenem and amoxicillin/clavulanate in combination with meropenem, colistin, or amikacin showed synergism against 60-70% isolates. On the other hand, in the biofilm state, colistin-based combinations exhibited synergism against 50-70% isolates and the most effective combination was colistin-amikacin with 70% synergy.
CONCLUSIONS
The results revealed that combinations of amoxicillin/clavulanate with colistin, meropenem, or amikacin in the planktonic mode and colistin with amoxicillin/clavulanate, meropenem, or amikacin in the biofilm mode could effectively inhibit CRKP isolates, and thus could be further explored for the treatment of CRKPs.
Topics: Humans; Meropenem; Colistin; Amikacin; Pneumonia, Ventilator-Associated; Klebsiella pneumoniae; Drug Synergism; Anti-Bacterial Agents; Klebsiella Infections; Amoxicillin-Potassium Clavulanate Combination; Microbial Sensitivity Tests
PubMed: 37864176
DOI: 10.1186/s12866-023-03039-w -
Antimicrobial Agents and Chemotherapy Feb 2022Biofilms colonize medical devices and are often recalcitrant to antibiotics. Interkingdom biofilms, where at least a bacterium and a fungus are present, increase the...
Biofilms colonize medical devices and are often recalcitrant to antibiotics. Interkingdom biofilms, where at least a bacterium and a fungus are present, increase the likelihood of therapeutic failures. In this work, a three-species biofilm model including Staphylococcus aureus, Escherichia coli, and Candida albicans was used to study the activity of the antibiotics moxifloxacin and meropenem, the antifungal caspofungin, and combinations of them against interkingdom biofilms. The culturable cells and total biomass were evaluated to determine the pharmacodynamic parameters of the drug response for the incubation with the drugs alone. The synergic or antagonistic effects (increased/decreased effects) of the combination of drugs were analyzed with the highest-single-agent method. Biofilms were imaged in confocal microscopy after live/dead staining. The drugs had limited activity when used alone against single-, dual-, and three-species biofilms. When used in combination, additive effects against single- and dual-species biofilms and increased effects (synergy) against biomass of three-species biofilms were observed. In addition, the two antibiotics showed different patterns, moxifloxacin being more active when targeting S. aureus and meropenem when targeting E. coli. All these observations were confirmed by confocal microscopy images. Our findings highlight the interest in combining caspofungin with antibiotics against interkingdom biofilms.
Topics: Antifungal Agents; Biofilms; Candida albicans; Caspofungin; Escherichia coli; Meropenem; Microbial Sensitivity Tests; Moxifloxacin; Staphylococcus aureus
PubMed: 34930026
DOI: 10.1128/AAC.02149-21 -
Journal of Global Antimicrobial... Jun 2023Little is known regarding outcomes and optimal therapeutic regimens of infections caused by Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp)...
Ceftazidime/avibactam-resistant meropenem-susceptible KPC-producing Klebsiella pneumoniae: Analysis of cases and evaluation of in vitro activity of fosfomycin-containing combinations.
OBJECTIVES
Little is known regarding outcomes and optimal therapeutic regimens of infections caused by Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) resistant to ceftazidime/avibactam (CZA) and susceptible to meropenem (MEM). Although susceptible to MEM in vitro, the possibility of developing MEM resistance overtime is a concern. We describe the clinical characteristics of patients with colonization/infection due to KPC variants with a focus on the in vitro activity of fosfomycin (FOS)-containing combinations.
METHODS
Patients with colonization/infection due to a KPC variant were included. Fosfomycin susceptibility was performed by agar dilution method. Synergistic activity of FOS-based combinations was evaluated by gradient strip-agar diffusion method. The emergence of in vitro MEM resistance was also tested.
RESULTS
Eleven patients were included: eight with infection [four with ventilator-associated pneumonia and four with bloodstream infections] and three with colonization. Previous therapy with CZA was administered to all patients (with a mean cumulative duration of 23 days). All subjects with infection received meropenem, in monotherapy (n = 4) or with amikacin (n = 2) or fosfomycin (n = 2), and achieved clinical cure. A new CZA-susceptible and MEM-resistant KPC-Kp strain was subsequently isolated in three patients (27.3%). Meropenem/vaborbactam (MVB) showed high in vitro activity, while FOS+MEM combination was synergistic in 40% of cases. In vitro resistance to MEM was observed with maintenance of CZA resistance.
CONCLUSIONS
Detection of KPC variants may occur within the same patient, especially if CZA has been previously administered. Although clinical success has been obtained with carbapenems, the emergence of MEM resistance is a concern. Fosfomycin plus meropenem is synergistic and may be a valuable combination option for KPC variants, while MVB may be considered in monotherapy. The detection of KPC variants in an endemic setting for KPC-Kp represents a worryingly emerging condition. The optimal therapeutic approach is still unknown and the development of meropenem resistance is of concern, which may lead to therapeutic failure in clinical practice. In these cases, the addition of fosfomycin to meropenem, or a more potent antibiotic, such as meropenem/vaborbactam, may be valuable therapeutic options.
Topics: Humans; Ceftazidime; Meropenem; Fosfomycin; Klebsiella pneumoniae; Agar; Klebsiella Infections
PubMed: 37086891
DOI: 10.1016/j.jgar.2023.03.012 -
The Journal of Antimicrobial... Sep 2021Meropenem/vaborbactam has been approved in Europe for the treatment of hospital-acquired bacterial pneumonia, ventilator-associated pneumonia (VAP) and bacteraemia among...
Activity of meropenem/vaborbactam and comparators against Gram-negative isolates from Eastern and Western European patients hospitalized with pneumonia including ventilator-associated pneumonia (2014-19).
OBJECTIVES
Meropenem/vaborbactam has been approved in Europe for the treatment of hospital-acquired bacterial pneumonia, ventilator-associated pneumonia (VAP) and bacteraemia among other indications. Vaborbactam is an inhibitor of class A and C β-lactamases, including Klebsiella pneumoniae carbapenemase (KPC) enzymes, but not class B or D carbapenemases. We analysed the activity of meropenem/vaborbactam and comparators against 6846 Enterobacterales and 3567 Pseudomonas aeruginosa isolates from patients hospitalized with pneumonia (PHP), including VAP.
METHODS
Isolates from PHP were consecutively collected during 2014-19 from 42 European hospitals located in 21 countries and susceptibility tested using the broth microdilution method. Carbapenem-resistant Enterobacterales (CRE) isolates were molecularly characterized to identify their carbapenem-resistance mechanisms. EUCAST (2020) interpretive criteria were used.
RESULTS
The most common Gram-negative pathogens isolated from PHP were P. aeruginosa (n = 3567), K. pneumoniae (n = 1877) and Escherichia coli (n = 1646). Overall, 98.0% of Enterobacterales and 82.1% of P. aeruginosa were susceptible to meropenem/vaborbactam, with 99.8% of Enterobacterales and 89.7% of P. aeruginosa in Western Europe (WE) and 92.7% of Enterobacterales and 69.1% of P. aeruginosa in Eastern Europe (EE). CRE were more common in EE (15.1%) than WE (2.1%). KPC was the most common carbapenemase in WE, while OXA-48-like was the most common carbapenemase in EE. Meropenem/vaborbactam susceptibility was 63.0% for all CRE (92.2% in WE and 51.5% in EE). Meropenem/vaborbactam inhibited 99.1% of KPC-producing isolates and 40.5% of OXA-48-like-producing isolates.
CONCLUSIONS
These in vitro data demonstrate that meropenem/vaborbactam has potent activity against isolates from PHP, including isolates producing KPC, and may be a useful treatment option for PHP, including VAP.
Topics: Anti-Bacterial Agents; Bacterial Proteins; Boronic Acids; Carbapenems; Humans; Meropenem; Microbial Sensitivity Tests; Pneumonia, Ventilator-Associated; beta-Lactamases
PubMed: 34302173
DOI: 10.1093/jac/dkab252