-
The Senior Care Pharmacist Mar 2019Meropenem-vaborbactam is a newly approved antibiotic for complex urinary tract infections and to treat carbapenem-resistant Enterobacteriaceae infections. Its advantage... (Review)
Review
Meropenem-vaborbactam is a newly approved antibiotic for complex urinary tract infections and to treat carbapenem-resistant Enterobacteriaceae infections. Its advantage over meropenem is the betalactamase inhibitor which slows bacterial resistance. This medication has been studied in numerous countries and has relatively few side effects. There were slightly higher incidences of alanine aminotransferase (ALT), aspartate aminotransferase (AST), elevations, infusion site phlebitis, but less anemia, vaginal infections, and discontinuation when compared with pipercacilin-tazobactam.
The combination drug's relevance for the geriatrician is that older adults are at higher risk for urinary tract infections (UTIs). Some drugs that had previously been prescribed are now less useful for treating UTIs. This leaves clinicians with drugs that have more side effects.
This new drug has two significant drug interactions. Meropenem competes with probenecid in the kidney's tubular secretion. This increases the concentration of meropenem. Meropenem lessens valproic acid blood levels, putting patients at risk for seizures. It is not known to impact cytochrome p450 enzymes. It comes as a dry powder and should be diluted in 250 mL of normal saline and given over a three-hour infusion.
Vaborbactam is not known to have drug interactions. Vaborbactam does not affect the cytochrome p450 enzymes. This antibiotic has been studied in patients as old as 92 years. Renal dose adjustment allows the medication to be administered safely at all stages of kidney disease. If a patient is on dialysis, it is to be given after dialysis. No dose adjustment is needed based on the Child-Pugh score (i.e., for hepatic function). Based on local resistance, it may be beneficial to add this medication to one's formulary.Topics: Anti-Bacterial Agents; Boronic Acids; Humans; Meropenem; Renal Dialysis
PubMed: 31155025
DOI: No ID Found -
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 -
Future Microbiology Sep 2022The authors aimed to determine the efficacy of frequently used antibiotics, alone or in combination, against biofilms of ventilator-associated pneumonia isolates. The...
The authors aimed to determine the efficacy of frequently used antibiotics, alone or in combination, against biofilms of ventilator-associated pneumonia isolates. The authors determined the MICs, minimum biofilm inhibitory concentrations and minimum biofilm eradication concentrations of meropenem, ciprofloxacin and colistin as well as their combinations against planktonic forms and biofilms of , and clinical isolates. Generally, the minimum biofilm inhibitory concentrations and minimum biofilm eradication concentrations of the antibiotics were 1000-fold higher than their MICs, and synergy was provided by different concentrations of meropenem-colistin and meropenem-ciprofloxacin combinations with checkerboard and time-kill curve methods. The combination of meropenem and ciprofloxacin seems to be a good candidate for the treatment of biofilm-associated infections; none of the concentrations obtained as a result of the synergy test were clinically significant.
Topics: Acinetobacter baumannii; Anti-Bacterial Agents; Biofilms; Ciprofloxacin; Colistin; Drug Synergism; Humans; Meropenem; Microbial Sensitivity Tests; Pneumonia, Ventilator-Associated
PubMed: 35796076
DOI: 10.2217/fmb-2021-0305 -
Journal of Biomaterials Applications Oct 2021The aims of the present study were the determination of antimicrobial and antibiofilm effects of meropenem-loaded mesoporous silica nanoparticles (MSNs) on carbapenem...
The aims of the present study were the determination of antimicrobial and antibiofilm effects of meropenem-loaded mesoporous silica nanoparticles (MSNs) on carbapenem resistant () and cytotoxicity properties . The meropenem-loaded MSNs had shown antibacterial and biofilm inhibitory activities on all isolates at different levels lower than MICs and BICs of meropenem. The viability of HC-04 cells treated with serial concentrations as MICs and BICs of meropenem-loaded MSNs was 92-100%. According to the obtained results, meropenem-loaded MSNs display the significant antibacterial and antibiofilm effects against carbapenem resistant and biofilm forming and low cell toxicity . Then, the prepared system can be an appropriate option for the delivery of carbapenem for further evaluation assays.
Topics: Anti-Bacterial Agents; Anti-Infective Agents; Biofilms; Carbapenem-Resistant Enterobacteriaceae; Carbapenems; Drug Resistance, Bacterial; Humans; Meropenem; Microbial Sensitivity Tests; Nanoparticles; Pseudomonas Infections; Pseudomonas aeruginosa; Silicon Dioxide
PubMed: 33722086
DOI: 10.1177/08853282211003848 -
Microbial Drug Resistance (Larchmont,... Jul 2022Colistin-based antibiotic therapies have been recommended for the treatment of multidrug-resistant infections. During colistin treatment, persister cells that tolerate...
Colistin-based antibiotic therapies have been recommended for the treatment of multidrug-resistant infections. During colistin treatment, persister cells that tolerate antibiotics may arise. Here we designed an study to assess the killing activity of colistin, meropenem, and amikacin on colistin-induced persisters in comparison with starvation-induced persisters. Colistin-induced persisters were generated under exposure to 10 × minimum inhibitory concentration dose of colistin, whereas starvation-induced persisters were produced by limitation of nutrients. In colistin-induced persisters, amikacin totally inhibited cell growth in 6 hours, whereas 98% of the cell population was inhibited by meropenem, and total eradication with meropenem was observed after 24 hours. Both antibiotics also inhibited metabolic activity >88%. The lack of killing effect under colistin exposure suggested to us that these cells could protect themselves from further colistin stress. There was no significant permeabilization change in the cellular membrane with all antibiotics. There was no killing effect on starvation-induced persister cells with the exposure to all antibiotics. In 6 hours, the metabolic activity of the persisters with meropenem and colistin increased 99% and 40%, respectively, whereas there was no increase with amikacin. The sustained inhibition with amikacin was an important finding for antipersister effect of amikacin. Amikacin had rapid and sustained antipersister activity on colistin-induced persister cells. During the colistin treatment of infection, the addition of amikacin to the regimen seems to be an effective approach to prevent a recurrence.
Topics: Amikacin; Anti-Bacterial Agents; Colistin; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests
PubMed: 35759379
DOI: 10.1089/mdr.2021.0207 -
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 -
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 -
European Journal of Medicinal Chemistry Mar 2023New Delhi metallo-β-lactamase-1 (NDM-1) is the most important and prevalent enzyme among all metallo-β-lactamases. NDM-1 can hydrolyze almost all-available β-lactam...
New Delhi metallo-β-lactamase-1 (NDM-1) is the most important and prevalent enzyme among all metallo-β-lactamases. NDM-1 can hydrolyze almost all-available β-lactam antibiotics including carbapenems, resulting in multidrug resistance, which poses an increasing clinical threat. However, there is no NDM-1 inhibitor approved for clinical treatment. Therefore, identifying a novel and potential enzyme inhibitor against NDM-1-mediated infections is an urgent need. In this study, vidofludimus was identified as a potential NDM-1 inhibitor by structure-based virtual screening and an enzyme activity inhibition assay. Vidofludimus significantly inhibited NDM-1 hydrolysis activity with a significant dose-dependent effect. When the vidofludimus concentration was 10 μg/ml, the inhibition rate and 50% inhibitory concentration were 93.3% and 13.8 ± 0.5 μM, respectively. In vitro, vidofludimus effectively restored the antibacterial activity of meropenem against NDM-1-positive Escherichia coli (E. coli), and the minimum inhibitory concentration of meropenem was decreased from 64 μg/ml to 4 μg/ml, a 16-fold reduction. The combination of vidofludimus and meropenem showed a significant synergistic effect with a fractional inhibitory concentration index of 0.125 and almost all the NDM-1-positive E. coli were killed within 12 h. Furthermore, the synergistic therapeutic effect of vidofludimus and meropenem in vivo was evaluated in mice infected with NDM-1 positive E. coli. Compared with the control treatment, vidofludimus combined with meropenem significantly improved the survival rate of mice infected with NDM-1-positive E. coli (P < 0.05), decreased the white blood cell count, the bacterial burden and inflammatory response induced by NDM-1-positive E. coli (P < 0.05), and alleviated histopathological damage in infected mice. It was demonstrated by molecular dynamic simulation, site-directed mutagenesis and biomolecular interaction that vidofludimus could interact directly with the key amino acids (Met67, His120, His122 and His250) and Zn in the active site of NDM-1, thereby competitively inhibiting the hydrolysis activity of NDM-1 on meropenem. In summary, vidofludimus holds promise as anNDM-1 inhibitor, and the combination of vidofludimus and meropenem has potential as a therapeutic strategy for NDM-1-mediated infections.
Topics: Animals; Mice; Meropenem; Escherichia coli; Anti-Bacterial Agents; beta-Lactamases; Enzyme Inhibitors; Microbial Sensitivity Tests; beta-Lactamase Inhibitors
PubMed: 36870273
DOI: 10.1016/j.ejmech.2023.115225 -
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