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The Journal of Antimicrobial... Jul 2018Sepsis and bacterial meningitis are major causes of mortality and morbidity in neonates and infants. Meropenem, a broad-spectrum antibiotic, is not licensed for use in... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Sepsis and bacterial meningitis are major causes of mortality and morbidity in neonates and infants. Meropenem, a broad-spectrum antibiotic, is not licensed for use in neonates and infants below 3 months of age and sufficient information on its plasma and CSF disposition and dosing in neonates and infants is lacking.
OBJECTIVES
To determine plasma and CSF pharmacokinetics of meropenem in neonates and young infants and the link between pharmacokinetics and clinical outcomes in babies with late-onset sepsis (LOS).
METHODS
Data were collected in two recently conducted studies, i.e. NeoMero-1 (neonatal LOS) and NeoMero-2 (neonatal meningitis). Optimally timed plasma samples (n = 401) from 167 patients and opportunistic CSF samples (n = 78) from 56 patients were analysed.
RESULTS
A one-compartment model with allometric scaling and fixed maturation gave adequate fit to both plasma and CSF data; the CL and volume (standardized to 70 kg) were 16.7 (95% CI 14.7, 18.9) L/h and 38.6 (95% CI 34.9, 43.4) L, respectively. CSF penetration was low (8%), but rose with increasing CSF protein, with 40% penetration predicted at a protein concentration of 6 g/L. Increased infusion time improved plasma target attainment, but lowered CSF concentrations. For 24 patients with culture-proven Gram-negative LOS, pharmacodynamic target attainment was similar regardless of the test-of-cure visit outcome.
CONCLUSIONS
Simulations showed that longer infusions increase plasma PTA but decrease CSF PTA. CSF penetration is worsened with long infusions so increasing dose frequency to achieve therapeutic targets should be considered.
Topics: Anti-Bacterial Agents; Europe; Female; Gram-Negative Bacterial Infections; Humans; Infant; Infant, Newborn; Infusions, Intravenous; Male; Meningitis, Bacterial; Meropenem; Monte Carlo Method; Neonatal Sepsis; Sepsis
PubMed: 29684147
DOI: 10.1093/jac/dky128 -
BMC Microbiology May 2023Acinetobacter baumannii is one of the main causes of healthcare-associated infections that threaten public health, and carbapenems, such as meropenem, have been a...
BACKGROUND
Acinetobacter baumannii is one of the main causes of healthcare-associated infections that threaten public health, and carbapenems, such as meropenem, have been a therapeutic option for these infections. Therapeutic failure is mainly due to the antimicrobial resistance of A. baumannii, as well as the presence of persister cells. Persisters constitute a fraction of the bacterial population that present a transient phenotype capable of tolerating supra-lethal concentrations of antibiotics. Some proteins have been suggested to be involved in the onset and/or maintenance of this phenotype. Thus, we investigated the mRNA levels of the adeB (AdeABC efflux pump component), ompA, and ompW (outer membrane proteins) in A. baumannii cells before and after exposure to meropenem.
RESULTS
We found a significant increase (p-value < 0.05) in the expression of ompA (> 5.5-fold) and ompW (> 10.5-fold) in persisters. However, adeB did not show significantly different expression levels when comparing treated and untreated cells. Therefore, we suggest that these outer membrane proteins, especially OmpW, could be part of the mechanism of A. baumannii persisters to deal with the presence of high doses of meropenem. We also observed in the Galleria mellonella larvae model that persister cells are more virulent than regular ones, as evidenced by their LD values.
CONCLUSIONS
Taken together, these data contribute to the understanding of the phenotypic features of A. baumannii persisters and their relation to virulence, as well as highlight OmpW and OmpA as potential targets for drug development against A. baumannii persisters.
Topics: Meropenem; Acinetobacter baumannii; Virulence; Anti-Bacterial Agents; Membrane Proteins; Microbial Sensitivity Tests; Bacterial Proteins
PubMed: 37246220
DOI: 10.1186/s12866-023-02904-y -
The Yale Journal of Biology and Medicine Dec 2022: Antibiotic resistance in cystic fibrosis (CF) is a well-known phenomenon. However, the comprehensive epidemiological impact of antibiotic resistance in CF is not... (Meta-Analysis)
Meta-Analysis Review
: Antibiotic resistance in cystic fibrosis (CF) is a well-known phenomenon. However, the comprehensive epidemiological impact of antibiotic resistance in CF is not clearly documented. So, this meta-analysis evaluated the proportion rates of carbapenem resistance (imipenem, meropenem, and doripenem) in CF based on publication date (1979-2000, 2001-2010, and 2011-2021), continents, pathogens, and antimicrobial susceptibility testing (AST). : We searched studies in PubMed, Scopus, and Web of Science (until April 2021). Statistical analyses were conducted using STATA software (version 14.0). : The 110 studies included in the analysis were performed in 25 countries and investigated 13,324 pathogens associated with CF. The overall proportion of imipenem, meropenem, and doripenem resistance in CF were 43% (95% CI 36-49), 48% (95% CI 40-57), 28% (95% CI 23-33), and 45% (95% CI 32-59), respectively. Our meta-analysis showed that trends of imipenem, meropenem, and doripenem-resistance had gradual decreases over time (1979-2021). This could be due to the limited clinical effectiveness of these antibiotics to treat CF cases over time. Among the opportunistic pathogens associated with CF, the highest carbapenem resistance rates were shown in , spp., , and . The highest and lowest carbapenem resistance rates among in CF patients were shown against meropenem (23%) and doripenem (39%). : We showed that trends of carbapenem resistance had decreased over time (1979-2021). This could be due to the limited clinical effectiveness of these antibiotics to treat CF cases over time. Plans should be directed to fight biofilm-associated infections and prevent the emergence of mutational resistance. Systematic surveillance for carbapenemase-producing pathogens in CF by molecular surveillance is necessitated.
Topics: Humans; Meropenem; Doripenem; Carbapenems; Cystic Fibrosis; Microbial Sensitivity Tests; Anti-Bacterial Agents; Imipenem; Pseudomonas aeruginosa
PubMed: 36568834
DOI: No ID Found -
Injury Aug 2022Cannulated screws are often used in the management of open lower extremity fractures. These fractures exhibit broad contamination profiles, necessitating empirical...
Concentrations of co-administered vancomycin and meropenem in the internal dead space of a cannulated screw and in cancellous bone adjacent to the screw - Evaluated by microdialysis in a porcine model.
BACKGROUND
Cannulated screws are often used in the management of open lower extremity fractures. These fractures exhibit broad contamination profiles, necessitating empirical Gram-positive and Gram-negative antibiotic coverage. To ensure full antibiotic protection of the cannulated screw and the bone tissue, it is generally accepted that target tissue antibiotic concentrations, as a minimum, reach and remain above relevant epidemiological cut-off minimal inhibitory concentrations (T>MIC) for a sufficient amount of time.
METHODS
8 female pigs were included. Microdialysis catheters were placed in the internal dead space of a cannulated screw placed in tibial cancellous bone, in tibial cancellous bone adjacent to the screw (mean distance to the screw: 3 mm), and in cancellous bone on the contralateral tibia. Following single-dose simultaneous intravenous administrations of vancomycin (1000 mg) and meropenem (1000 mg), microdialysates and plasma were dynamically sampled over 8 h. The applied MIC targets ranged from 1 to 4 µg/mL for vancomycin and 0.125-2 µg/mL for meropenem RESULTS: For both drugs, and for all MIC targets investigated (except for the high vancomycin target: 4 µg/mL), the internal dead space of the cannulated screw had the shortest T>MIC. At the low MIC targets T>MIC ranged between 88 and 449 min across sampling sites for vancomycin (1 µg/mL), and 148-406 min for meropenem (0.125 µg/mL). For the high MIC targets, T>MIC ranged between 3 and 446 min for vancomycin (4 μg/mL) and 17-181 min for meropenem (2 μg/mL). Vancomycin displayed longer T>MIC (2 and 4 μg/mL), higher area under the concentration time curve (AUC) and peak drug concentration in the proximal tibial cancellous bone without a screw nearby. For meropenem, only the cancellous bone AUC was significantly higher on the side with no screw.
CONCLUSION
We found short T>MIC, particularly for the high MIC targets for vancomycin and meropenem, both inside the cannulated screw and in cancellous bone adjacent to the screw. The presence of a cannulated screw impaired the penetration of especially vancomycin into cancellous bone adjacent to the screw. More aggressive or different vancomycin and meropenem approaches may be considered to encompass contaminating differences and to ensure a theoretically more sufficient antibiotic protection of cannulated screws when used in the management of open lower extremity fractures.
Topics: Animals; Anti-Bacterial Agents; Cancellous Bone; Female; Meropenem; Microdialysis; Swine; Vancomycin
PubMed: 35710595
DOI: 10.1016/j.injury.2022.06.008 -
Drugs Feb 2019Eravacycline (Xerava™), a novel fully synthetic fluorocycline, consists of the tetracyclic core scaffold with unique modifications in the tetracyclic D ring;... (Review)
Review
Eravacycline (Xerava™), a novel fully synthetic fluorocycline, consists of the tetracyclic core scaffold with unique modifications in the tetracyclic D ring; consequently, it exhibits potent in vitro activity against Gram-positive and -negative bacterial strains expressing certain common tetracycline-specific acquired resistance mechanisms. In vitro, eravacycline exhibits potent activity against a broad spectrum of clinically relevant Gram-positive and -negative aerobic and anaerobic bacteria. Intravenous eravacycline is approved in several countries for the treatment of complicated intra-abdominal infections (cIAIs) in adult patients. In two pivotal double-blind, multinational trials in this patient population, eravacycline (infusion ≈ 1 h) was noninferior to intravenous ertapenem or meropenem at the test-of-cure visit in terms of clinical response rates in all prespecified populations. Eravacycline had an acceptable tolerability profile, with infusion site reactions, nausea, vomiting and diarrhoea the most commonly reported adverse reactions, most of which were of mild to moderate severity. Given its broad spectrum of activity against common clinically relevant pathogens (including those expressing certain tetracycline- and other antibacterial-specific acquired resistance mechanisms) and its more potent in vitro activity and better tolerability profile than tigecycline, eravacycline provides a novel emerging option for the treatment of adult patients with cIAIs, especially as empirical therapy when coverage of resistant pathogens is required.
Topics: Anti-Bacterial Agents; Dose-Response Relationship, Drug; Drug Resistance, Multiple, Bacterial; Ertapenem; Humans; Intraabdominal Infections; Meropenem; Randomized Controlled Trials as Topic; Tetracyclines; Tigecycline
PubMed: 30783960
DOI: 10.1007/s40265-019-01067-3 -
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 -
International Journal of Antimicrobial... Jan 2024To illustrate the impact of errors in documented dose administration time on therapeutic drug monitoring (TDM)-based target attainment evaluation for vancomycin and...
OBJECTIVES
To illustrate the impact of errors in documented dose administration time on therapeutic drug monitoring (TDM)-based target attainment evaluation for vancomycin and meropenem, and to explore the influence of drug and patient characteristics, and TDM sampling strategies.
METHODS
Bedside observations of errors in documented dose administration times were collected. Population pharmacokinetic simulations were performed for vancomycin and meropenem, evaluating different one- and two-sampling strategies for populations with estimated creatinine clearance (CLcr) of 30, 80 or 130 mL/min. The impact of errors was evaluated as the proportion of individuals incorrectly considered to have reached the target.
RESULTS
Of 143 observed dose administrations, 97% of doses were given within ±30 min of the documented time. For vancomycin, a +30 min error was predicted to result in a 0.1-3.9 percentage point increase of cases incorrectly evaluated as reaching area under the concentration-time curve during a 24-hour period (AUC)/minimum inhibitory concentration (MIC) >400, with the largest increase for patients with augmented renal clearance and peak and trough sampling. For meropenem, a +30 min error resulted in a 1.3-6.4 and 0-20 percentage point increase of cases incorrectly evaluated as reaching 100% T, and 50% T, respectively. Overall, mid-dose and trough sampling was most favourable for both antibiotics.
CONCLUSIONS
For vancomycin, simulations indicate that TDM-based target attainment evaluation is robust with respect to the observed errors in dose administration time of ±30 min; however, the errors had a potentially clinically important impact in patients with augmented renal clearance. For meropenem, extra measures to promote correct documentation are warranted when using TDM, as the impact of errors was evident even in patients with normal renal function.
Topics: Humans; Vancomycin; Meropenem; Drug Monitoring; Anti-Bacterial Agents; Kidney Function Tests; Renal Insufficiency
PubMed: 37956952
DOI: 10.1016/j.ijantimicag.2023.107032 -
Molecules (Basel, Switzerland) Jun 2023Copper (Cu) is an essential trace metal and its concentration in body plasma is tightly regulated. An increase in Cu concentration in body fluids is observed in numerous... (Review)
Review
Copper (Cu) is an essential trace metal and its concentration in body plasma is tightly regulated. An increase in Cu concentration in body fluids is observed in numerous pathological conditions, including infections caused by microorganisms. Evidence shows that Cu ions can impact the activity of antibiotics by increasing efficiency or diminishing/neutralizing antibiotic activity, forming complexes which may lead to antibiotic structure degradation. Herein, we represent the evidence available on Cu-antibiotic interactions and their possible impact on antimicrobial therapy efficiency. So far, in vitro studies described interactions between Cu ions and the majority of antibiotics in clinical use: penicillins, cephalosporins, carbapenems, macrolides, aminoglycosides, tetracyclines, fluoroquinolones, isoniazid, metronidazole. In vitro-described degradation or lower antimicrobial activity of amoxicillin, ampicillin, cefaclor, ceftriaxone, and meropenem in the presence of Cu ions suggest caution when using prescribed antibiotics in patients with altered Cu levels. On the other hand, several Cu-dependent compounds with antibacterial activity including the drug-resistant bacteria were discovered, such as thiosemicarbazones, disulfiram, dithiocarbamates, 8-hydroxiquinoline, phenanthrolines, pyrithione. Having in mind that the development of new antibiotics is already marked as inadequate and does not meet global needs, the potential of Cu-antibiotic interactions to change the efficiency of antimicrobial therapy requires further investigation.
Topics: Humans; Copper; Anti-Bacterial Agents; Meropenem; Ampicillin; Ions
PubMed: 37446795
DOI: 10.3390/molecules28135133 -
Microbiology Spectrum Feb 2023Carbapenems are a common first-line therapy for serious Gram-negative infections, but carbapenem-resistant (CRE) isolates have become an urgent health concern....
Carbapenems are a common first-line therapy for serious Gram-negative infections, but carbapenem-resistant (CRE) isolates have become an urgent health concern. Klebsiella pneumoniae serine carbapenemases (KPCs) now have been disseminated worldwide and are endemic in many hospitals globally. Isolates producing metallo-β-lactamases (MBLs) or class D OXA-48 carbapenemases are also increasingly common in Europe, although they are less common in the United States. Meropenem-vaborbactam is a combination of the carbapenem meropenem and vaborbactam, which is a β-lactamase inhibitor with activity against serine carbapenemases, including KPC-producing isolates. We examined the susceptibility of U.S. multidrug-resistant (MDR) isolates to meropenem-vaborbactam. A total of 1,697 MDR isolates were collected in 31 U.S. medical centers in 2016 to 2020. Susceptibility testing was performed using the Clinical and Laboratory Standards Institute (CLSI) broth microdilution method. Whole-genome sequencing was performed for all CRE strains (MIC values of >2 mg/L for imipenem or meropenem). The rate of susceptibility of all MDR strains to meropenem-vaborbactam was 99.1%, and 86.2% of the isolates were susceptible to meropenem. There were 222 CRE isolates (13.1%). KPC was the most common carbapenemase (81.1%). Thirteen CRE isolates produced NDM (= 7), VIM (= 3), and/or OXA-48-like (= 4) carbapenemases; 29 CRE isolates (13.1%) had no detected carbapenemase. The rate of susceptibility of all CRE strains to meropenem-vaborbactam was 93.2%, and the rate of susceptibility of the KPC-producing isolates to meropenem-vaborbactam was 98.9%. The primary carbapenemase in the United States continues to be KPC, while MBL and OXA-48-like carbapenemases remain uncommon. Overall, the rate of susceptibility of these U.S. MDR organisms to meropenem-vaborbactam was 99.1%, indicating that meropenem-vaborbactam is a valuable treatment option for Gram-negative infections caused by U.S. MDR organisms. Carbapenems are a common first-line therapy for serious Gram-negative infections, but CRE isolates have become an urgent health concern. Meropenem-vaborbactam is a combination of the carbapenem meropenem and vaborbactam, which is a β-lactamase inhibitor with activity against serine carbapenemases, including KPC-producing isolates. We examined the susceptibility of U.S. MDR Gram-negative isolates to meropenem-vaborbactam. A total of 1,697 U.S. MDR isolates collected in 2016 to 2020 were tested. Susceptibility testing was performed using the CLSI broth microdilution method. Whole-genome sequencing was performed for all CRE strains (MIC values of >2 mg/L for imipenem or meropenem). The rate of susceptibility of all MDR strains to meropenem-vaborbactam was 99.1%, and 86.2% of the isolates were susceptible to meropenem. A total of 13.1% of the isolates were CRE strains, and KPC was the most common carbapenemase. Overall, the rate of susceptibility of these U.S. MDR organisms to meropenem-vaborbactam indicates that meropenem-vaborbactam is a valuable treatment option for Gram-negative infections caused by U.S. MDR Gram-negative pathogens.
Topics: United States; Meropenem; Carbapenems; Anti-Bacterial Agents; beta-Lactamase Inhibitors; Bacterial Proteins; Imipenem; beta-Lactamases; Gram-Negative Bacteria; Gammaproteobacteria; Serine; Microbial Sensitivity Tests
PubMed: 36622238
DOI: 10.1128/spectrum.04507-22