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Clinical Therapeutics Aug 2020The objective of this communication was to determine the intravenous compatibility of ceftazidime/avibactam and aztreonam using simulated and actual Y-site...
PURPOSE
The objective of this communication was to determine the intravenous compatibility of ceftazidime/avibactam and aztreonam using simulated and actual Y-site administration.
METHODS
Ceftazidime-avibactam was reconstituted and diluted to concentrations of 8, 25, and 50 mg/mL in 0.9% sodium chloride. Aztreonam was reconstituted and diluted to concentrations of 10 and 20 mg/mL. Each combination of concentrations was tested for compatibility using visual, Tyndall beam, microscopy, turbidity, and pH assessments. Microscopy results were compared to those from sodium chloride 0.9% in water, pH was compared to that at time 0, and turbidity of combinations was compared to that of individual agents. Actual Y-site mixing was conducted over 2-h infusions with samples collected at 0, 1, and 2 h. Test results were evaluated at 0, 1, 2, 4, 8, and 12 h after mixing. All experiments were completed in triplicate.
FINDINGS
Across simulated and actual Y-site experiments, no evidence of incompatibility between combinations of ceftazidime-avibactam + aztreonam was observed. Visual and microscopic tests revealed no particulate matter, color changes, or turbidity. Tyndall beam tests were negative with all combinations. No evidence of incompatibility was observed in turbidity testing. The pH values were consistent across each of the 6 combinations, from immediately after mixing until 12 h after mixing. When the addition of agents was reversed in simulated Y-site experiments, no differences in compatibility were observed. No differences in compatibility between actual and simulated Y-site administration were observed, and there was minimal variability across all replicate experiments.
IMPLICATIONS
Ceftazidime-avibactam, at concentrations of 8, 25, and 50 mg/mL, appeared compatible with aztreonam at concentrations of 10 and 20 mg/mL.
Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Aztreonam; Ceftazidime; Computer Simulation; Drug Combinations; Drug Incompatibility; Infusions, Intravenous
PubMed: 32684326
DOI: 10.1016/j.clinthera.2020.06.005 -
Frontiers in Cellular and Infection... 2023To evaluate the efficacy of ceftazidime-avibactam (CZA) and aztreonam-avibactam (AZA) against bloodstream infections (BSIs) or lower respiratory tract infections (LRTIs)...
Optimal treatment of ceftazidime-avibactam and aztreonam-avibactam against bloodstream infections or lower respiratory tract infections caused by extensively drug-resistant or pan drug-resistant (XDR/PDR) .
OBJECTIVE
To evaluate the efficacy of ceftazidime-avibactam (CZA) and aztreonam-avibactam (AZA) against bloodstream infections (BSIs) or lower respiratory tract infections (LRTIs) - caused by extensive drug-resistant or pan drug-resistant (XDR/PDR)
METHOD
The two-fold dilution method was used to determine the minimum inhibitory concentrations (MICs) of CZA/AZA against XDR/PDR . Whole-genome sequencing was used to analyze the resistance determinants of each isolate. Monte Carlo simulations (MCSs) were used to evaluate the probability of target attainment (PTA) and the cumulative fraction of response (CFR) of each CZA/AZA dosing regimen traditional infusion (TI)/optimized two-step-administration therapy (OTAT).
RESULTS
We found that XDR/PDR P. aeruginosa may carry some rare MBLs (e.g.: IND-6, SLB-1, THIN-B). isolates producing IMP-45, VIM-1, or VIM-2 were inhibited by AZA at a concentration of 2 to 8 mg/L. All isolates producing IND-6 plus other serine β-lactamases were high-level resistant to CZA/AZA (MICs >64 mg/L). All simulated dosing regimens of CZA/AZA against BSIs-causing XDR/PDR achieved 100% PTA when the MIC was ≤32 mg/L.
CONCLUSION
AZA has been considered as an option for the treatment of infections caused by XDR/PDR producing IMP-45, VIM-1, or VIM-2. OTAT with sufficient pharmacodynamic exposure may be an optimal treatment option for XDR/PDR with a high-level MIC of CZA/AZA.
Topics: Humans; Aztreonam; Anti-Bacterial Agents; Pseudomonas aeruginosa; Pharmaceutical Preparations; Drug Combinations; Respiratory Tract Infections; Sepsis; beta-Lactamases; Microbial Sensitivity Tests; Pseudomonas Infections
PubMed: 37457958
DOI: 10.3389/fcimb.2023.1023948 -
The Journal of Antimicrobial... Nov 2021Multi-drug resistant (MDR) Gram-negative bacteria represent a growing threat, with an increasing prevalence of carbapenem-resistant Enterobacterales (CRE) infections,... (Review)
Review
Multi-drug resistant (MDR) Gram-negative bacteria represent a growing threat, with an increasing prevalence of carbapenem-resistant Enterobacterales (CRE) infections, for which treatment options are limited. New treatment combinations composed of a β-lactam antibiotic plus a potent β-lactamase inhibitor (BLI) with anti-carbapenemase activity have been developed, including two carbapenem/BLI combinations that are commercially available-meropenem/vaborbactam (Vabomere® in the US, Vaborem® in Europe; Melinta Therapeutics) and imipenem/cilastatin/relebactam (Recarbrio®; Merck Sharp & Dohme), plus one other (meropenem/nacubactam) in early clinical development. This review provides a summary of the preclinical evidence supporting the use of carbapenem/BLI combinations and presents the clinical evidence across a range of MDR Gram-negative infections, with a focus on the use of meropenem/vaborbactam. All three BLIs have shown in vivo activity against Klebsiella pneumoniae carbapenemase and other class A carbapenemases. In 2019, meropenem/vaborbactam was listed in the WHO's list of essential medicines, because of its activity against priority 1 antibiotic-resistant pathogens. Meropenem/vaborbactam has considerable in vitro and in vivo activity against CRE, and in vitro evidence showing a low potential for resistance at clinically relevant doses. In randomized trials, meropenem/vaborbactam was non-inferior to piperacillin/tazobactam in patients with complicated urinary tract infection and more effective than the best-available treatment in patients with serious CRE infections. Meropenem/vaborbactam is well tolerated and, based on clinical experience, demonstrated lower toxicity compared with the combination regimens that have previously been the standard of care. In conclusion, carbapenem/BLI combinations represent an important therapeutic strategy in patients with MDR Gram-negative infections.
Topics: Anti-Bacterial Agents; Carbapenems; Drug Resistance, Multiple, Bacterial; Humans; Monobactams; beta-Lactamase Inhibitors
PubMed: 34849998
DOI: 10.1093/jac/dkab353 -
Drug Development Research Nov 2023Drug addiction as a problem for the health of the individual and the society is the result of a complex process in which there is an interaction between brain nuclei and... (Review)
Review
Drug addiction as a problem for the health of the individual and the society is the result of a complex process in which there is an interaction between brain nuclei and neurotransmitters (such as glutamate). β-lactam antibiotics, due to their enhancing properties on the glutamate transporter glutamate transporter-1, can affect and counteract the addictive mechanisms of drugs through the regulation of extracellular glutamate. Since glutamate is a key neurotransmitter in the development of drug addiction, it seems that β-lactams can be considered as a promising treatment for addiction. However, more research in this field is necessary to identify other mechanisms involved in their effectiveness. This article is a review of the studies conducted on the effect of β-lactam administration in preventing the development of drug addiction, as well as their possible cellular and molecular mechanisms. This review suggests the clinical use of β-lactam antibiotics that have weak antimicrobial properties (such as clavulanic acid) in the treatment of drug dependence.
Topics: Humans; beta-Lactams; Monobactams; Substance-Related Disorders; Anti-Bacterial Agents; Amino Acid Transport System X-AG; Glutamates
PubMed: 37602907
DOI: 10.1002/ddr.22110 -
Clinical Infectious Diseases : An... May 2023Sulbactam-durlobactam is a β-lactam/β-lactamase inhibitor combination currently in development for the treatment of infections caused by Acinetobacter, including... (Review)
Review
The Pharmacokinetics/Pharmacodynamic Relationship of Durlobactam in Combination With Sulbactam in In Vitro and In Vivo Infection Model Systems Versus Acinetobacter baumannii-calcoaceticus Complex.
Sulbactam-durlobactam is a β-lactam/β-lactamase inhibitor combination currently in development for the treatment of infections caused by Acinetobacter, including multidrug-resistant (MDR) isolates. Although sulbactam is a β-lactamase inhibitor of a subset of Ambler class A enzymes, it also demonstrates intrinsic antibacterial activity against a limited number of bacterial species, including Acinetobacter, and has been used effectively in the treatment of susceptible Acinetobacter-associated infections. Increasing prevalence of β-lactamase-mediated resistance, however, has eroded the effectiveness of sulbactam in the treatment of this pathogen. Durlobactam is a rationally designed β-lactamase inhibitor within the diazabicyclooctane (DBO) class. The compound demonstrates a broad spectrum of inhibition of serine β-lactamase activity with particularly potent activity against class D enzymes, an attribute which differentiates it from other DBO inhibitors. When combined with sulbactam, durlobactam effectively restores the susceptibility of resistant isolates through β-lactamase inhibition. The present review describes the pharmacokinetic/pharmacodynamic (PK/PD) relationship associated with the activity of sulbactam and durlobactam established in nonclinical infection models with MDR Acinetobacter baumannii isolates. This information aids in the determination of PK/PD targets for efficacy, which can be used to forecast efficacious dose regimens of the combination in humans.
Topics: Humans; Sulbactam; beta-Lactamase Inhibitors; Acinetobacter baumannii; Anti-Bacterial Agents; Acinetobacter Infections; Monobactams; beta-Lactamases; Microbial Sensitivity Tests
PubMed: 37125469
DOI: 10.1093/cid/ciad096 -
Clinical Pharmacokinetics Jan 2023(Patho)physiological changes in older people may influence the pharmacokinetics (PK), and consequently the target attainment, of ß-lactam antibiotics using standard... (Review)
Review
BACKGROUND AND OBJECTIVE
(Patho)physiological changes in older people may influence the pharmacokinetics (PK), and consequently the target attainment, of ß-lactam antibiotics using standard dosing regimens. This systematic review compiles the current knowledge on the PK and target attainment of ß-lactam antibiotics in older people, with the aim to identify priorities for dose optimization in this patient population.
METHODS
A systematic literature search of the PubMed and EMBASE databases was conducted. Relevant articles published prior to 1 December 2021 were identified as eligible when they included data on the PK of ß-lactam antibiotics in adults ≥ 65 years of age. Extracted information included reported PK parameters (volume of distribution, clearance [CL], elimination rate constant, intercompartmental CL, elimination half-life, area under the concentration-time curve, maximum and trough concentration), covariates on PK parameters, target attainment rate, and dosing recommendations.
RESULTS
Ninety-one relevant articles were included in this review. Four main ß-lactam subclasses were represented: 59.3% on cephalosporins + cephamycins, 25.3% on penicillins, 15.4% on carbapenems, and 3.3% on monobactams; 65.9% of articles involved intravenous administration, 16.5% mixed administration routes, 12.1% oral administration, and 5.5% intramuscular administration. The majority of studies had a small sample size, often did not include detailed information on the study population and methods, and were fairly old. CL was, on average, decreased, while elimination half-life was prolonged in aged subjects compared with young subjects. Volume of distribution was generally similar between age groups. Most studies identified renal function as the most important contributor to altered drug CL. In only 30.8% of the articles, target attainment was studied, and in 35.7% of these articles, target attainment was found to be suboptimal. Dosing recommendations were incorporated in 87.9% of articles.
CONCLUSION
Studies frequently fail to provide an evidence-based dosing recommendation for this diverse patient population. Model-based PK studies that address both physiological and disease-related changes are urgently needed. This review identified gaps of knowledge to set priorities for further research.
Topics: Adult; Humans; Aged; Anti-Bacterial Agents; Cephalosporins; Monobactams; Penicillins; Lactams
PubMed: 36633814
DOI: 10.1007/s40262-022-01196-1 -
Bioorganic Chemistry Jan 2020Based on the structural characteristics of aztreonam (AZN) and its target PBP3, a series of new monobactam derivatives bearing various substituents on oxime residue were...
Based on the structural characteristics of aztreonam (AZN) and its target PBP3, a series of new monobactam derivatives bearing various substituents on oxime residue were prepared and evaluated for their antibacterial activities against susceptible and resistant Gram-negative bacteria. Among them, compounds 8p and 8r displayed moderate potency with MIC values of 0.125-32 μg/mL against most tested Gram-negative strains, comparable to AZN. Meanwhile, the combination of 8p and 8r with avibactam as a β-lactamases inhibitor, in a ratio of 1:16, showed a promising synergistic effect against both ESBLs- and NDM-1-producing K. pneumoniae, with significantly reduced MIC values up to 8-fold and >256-fold respectively. Furthermore, both of them demonstrated excellent safety profiles both in vitro and in vivo. The results provided powerful information for further structural optimization of monobactam antibiotics to fight β-lactamase-producing resistant Gram-negative bacteria.
Topics: Anti-Bacterial Agents; Dose-Response Relationship, Drug; Escherichia coli; Klebsiella pneumoniae; Microbial Sensitivity Tests; Molecular Structure; Monobactams; Oximes; Structure-Activity Relationship
PubMed: 31831161
DOI: 10.1016/j.bioorg.2019.103487 -
Transboundary and Emerging Diseases Sep 2022The primary goals of this cross-sectional study were to screen various food/water, and human samples for the presence of Salmonella species, and to assess the phenotypic...
The primary goals of this cross-sectional study were to screen various food/water, and human samples for the presence of Salmonella species, and to assess the phenotypic and genetic relationship between resistances found in food and human Salmonella isolates to critically important antibiotics. Between November 2019 and May 2021, 501 samples were randomly collected for Salmonella isolation and identification using standard culturing methods, biochemical, matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and PCR techniques. Antimicrobial susceptibility testing was performed on confirmed Salmonella species, and PCR was used to investigate the genetic components that confer these resistance traits. Salmonella enterica subspecies enterica was confirmed in 35 (6.99%) of the samples (raw food = 23, ready-to-eat food/drink [REF/D] = 5, human = 7). Seventeen of them were antibiotic-resistant to at least one class, and eight were multidrug-resistant (MDR) isolates (raw food = 7, human = 1). All Salmonella isolates were susceptible to carbapenems, third- and fourth-generation cephalosporins and monobactam antibiotics. Resistance phenotypes to aminoglycosides (48.57%), β-lactams (20%) and tetracycline (17.14%), as well as associated genes such as aadA, bla , bla and tetA, as well as dfrA and sul1, were prevalent in Salmonella isolates. Colistin resistance genotype (mcr1) was detected in three (8.57%) isolates recovered from egg, cattle mince and rabbit meat, and the total incidence was 14.29% when two isolates exhibited resistance phenotypes were considered. Furthermore, four (11.43%) MDR isolates shared the bla and bla genes, and one (2.86%) isolate contained three extended spectrum β-lactams producing genes (ESBL), namely bla , bla and bla . The gyrA gene was expressed by one of three foodborne Salmonella isolates (8.57%) with ciprofloxacin resistance phenotypes. To the best of our knowledge, this is the first report from Egypt identifying colistin resistance in Salmonella enterica recovered from cattle minced meat and rabbit meat. Overall, the highest incidence rate of Salmonella enterica was found in cattle-derived products, and it was slightly more prevalent in RTE/D foods than in raw foods. Resistance to critical and clinically important antibiotics, particularly in Salmonella from RTE/D food, suggests that these antibiotics are being abused in the investigated area's veterinary field, and raises the potential of these isolates being transmitted to high-risk humans, which would be a serious problem. Future research using whole-genome sequencing is needed to clarify Salmonella resistance mechanisms to critically important antimicrobial agents or those exhibiting multidrug resistance.
Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Carbapenems; Cattle; Cephalosporins; Ciprofloxacin; Colistin; Cross-Sectional Studies; Drug Resistance, Multiple, Bacterial; Humans; Microbial Sensitivity Tests; Monobactams; Prevalence; Rabbits; Salmonella; Salmonella enterica; Tetracyclines; beta-Lactamases; beta-Lactams
PubMed: 35396929
DOI: 10.1111/tbed.14553 -
MBio Feb 2023The purine-derived signaling molecules c-di-AMP and (p)ppGpp control /PBP2a-mediated β-lactam resistance in methicillin-resistant Staphylococcus aureus (MRSA) raise the...
The purine-derived signaling molecules c-di-AMP and (p)ppGpp control /PBP2a-mediated β-lactam resistance in methicillin-resistant Staphylococcus aureus (MRSA) raise the possibility that purine availability can control antibiotic susceptibility. Consistent with this, exogenous guanosine and xanthosine, which are fluxed through the GTP branch of purine biosynthesis, were shown to significantly reduce MRSA β-lactam resistance. In contrast, adenosine (fluxed to ATP) significantly increased oxacillin resistance, whereas inosine (which can be fluxed to ATP and GTP via hypoxanthine) only marginally increased oxacillin susceptibility. Furthermore, mutations that interfere with purine synthesis ( operon), transport (NupG, PbuG, PbuX) and the salvage pathway (DeoD2, Hpt) increased β-lactam resistance in MRSA strain JE2. Increased resistance of a mutant was not significantly reversed by guanosine, indicating that NupG is required for guanosine transport, which is required to reduce β-lactam resistance. Suppressor mutants resistant to oxacillin/guanosine combinations contained several purine salvage pathway mutations, including and . Guanosine significantly increased cell size and reduced levels of c-di-AMP, while inactivation of GdpP, the c-di-AMP phosphodiesterase negated the impact of guanosine on β-lactam susceptibility. PBP2a expression was unaffected in or mutants, suggesting that guanosine-induced β-lactam susceptibility may result from dysfunctional c-di-AMP-dependent osmoregulation. These data reveal the therapeutic potential of purine nucleosides, as β-lactam adjuvants that interfere with the normal activation of c-di-AMP are required for high-level β-lactam resistance in MRSA. The clinical burden of infections caused by antimicrobial resistant (AMR) pathogens is a leading threat to public health. Maintaining the effectiveness of existing antimicrobial drugs or finding ways to reintroduce drugs to which resistance is widespread is an important part of efforts to address the AMR crisis. Predominantly, the safest and most effective class of antibiotics are the β-lactams, which are no longer effective against methicillin-resistant Staphylococcus aureus (MRSA). Here, we report that the purine nucleosides guanosine and xanthosine have potent activity as adjuvants that can resensitize MRSA to oxacillin and other β-lactam antibiotics. Mechanistically, exposure of MRSA to these nucleosides significantly reduced the levels of the cyclic dinucleotide c-di-AMP, which is required for β-lactam resistance. Drugs derived from nucleotides are widely used in the treatment of cancer and viral infections highlighting the clinical potential of using purine nucleosides to restore or enhance the therapeutic effectiveness of β-lactams against MRSA and potentially other AMR pathogens.
Topics: Methicillin-Resistant Staphylococcus aureus; Purine Nucleosides; Bacterial Proteins; Anti-Bacterial Agents; Oxacillin; beta-Lactams; Monobactams; Guanosine; Adenosine Triphosphate; Guanosine Triphosphate; Microbial Sensitivity Tests; Penicillin-Binding Proteins; beta-Lactam Resistance
PubMed: 36507833
DOI: 10.1128/mbio.02478-22 -
Journal of Pharmaceutical and... Feb 2022To comply with regulatory requirements, it is necessary to detect and separate the impurities generated during aztreonam synthesis or storage. The chromatogram of...
To comply with regulatory requirements, it is necessary to detect and separate the impurities generated during aztreonam synthesis or storage. The chromatogram of aztreonam revealed eight major impurities, which were purified through medium-pressure reversed-phase column and preparative High Performance Liquid Chromatography (HPLC). Through high resolution electrospray ionization mass spectroscopy (HRESIMS), as well as one- and two-dimensional nuclear magnetic resonance (NMR), their structures were confirmed as aztreonam acetate (Ⅰ), desulfated aztreonam (Ⅱ), anti-aztreonam (Ⅲ), open-ring aztreonam (Ⅳ), open-ring desulfated aztreonam (Ⅴ), open-ring desulfated aztreonam ethyl ester (VI), cis-deamino open-ring desulfated aztreonam (VII), and trans-deamino open-ring desulfated aztreonam (Ⅷ). Their exact concentrations were determined through quantitative nuclear magnetic resonance (qNMR) technique. Structural elucidation of the eight impurities through H NMR, C NMR, the H-H COSY, NOESY, HSQC, HMBC NMR and MS spectra was conducted. Especially, ⅥI and Ⅷ were identified as undescribed impurities here.
Topics: Aztreonam; Chromatography, High Pressure Liquid; Drug Contamination; Magnetic Resonance Spectroscopy; Spectrometry, Mass, Electrospray Ionization
PubMed: 35026590
DOI: 10.1016/j.jpba.2022.114587