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Clinical Infectious Diseases : An... Jun 2024We report a fatal case of New Delhi metallo-β-lactamase (NDM)-producing Escherichia coli in a bacteremic patient with sequential failure of aztreonam plus...
Sequential Treatment Failure With Aztreonam-Ceftazidime-Avibactam Followed by Cefiderocol Due to Preexisting and Acquired Mechanisms in a New Delhi Metallo-β-lactamase-Producing Escherichia coli Causing Fatal Bloodstream Infection.
We report a fatal case of New Delhi metallo-β-lactamase (NDM)-producing Escherichia coli in a bacteremic patient with sequential failure of aztreonam plus ceftazidime-avibactam followed by cefiderocol. Acquired resistance was documented phenotypically and mediated through preexisting and acquired mutations. This case highlights the need to rethink optimal treatment for NDM-producing organisms.
Topics: Humans; Azabicyclo Compounds; beta-Lactamases; Aztreonam; Drug Combinations; Ceftazidime; Anti-Bacterial Agents; Escherichia coli; Escherichia coli Infections; Fatal Outcome; Cefiderocol; Bacteremia; Cephalosporins; Treatment Failure; Microbial Sensitivity Tests; Male; Drug Resistance, Multiple, Bacterial
PubMed: 38289725
DOI: 10.1093/cid/ciad759 -
Journal of Pharmaceutical and... Apr 2024Endometriosis is a gynecological disease that causes severe chronic pelvic pain and infertility in women. The therapeutic efficacy of the traditional herbal combination...
Integration of 16 S rRNA gene sequencing, metabonomics and metagenome analysis to investigate the mechanism of Sparganium stoloniferum-Curcuma phaeocaulis in treating of endometriosis in rats.
BACKGROUND
Endometriosis is a gynecological disease that causes severe chronic pelvic pain and infertility in women. The therapeutic efficacy of the traditional herbal combination of Sparganium stoloniferum-Curcuma phaeocaulis (Sangleng-Ezhu, SL-EZ) in the treatment of endometriosis has been established. However, the precise mechanism by which this treatment exerts its effects remains elusive.
METHODS
To gain further insights, UPLC-MS/MS was employed to identify the primary chemical constituents of SL-EZ in serum. Additionally, network pharmacology was utilized to analyze the active ingredients and their corresponding targets. Furthermore, the impact of SL-EZ on ectopic endometrial growth in endometrial implants was assessed using a rat model. The therapeutic mechanism of SL-EZ in rats with endometriosis was further investigated through the application of 16 S rRNA gene sequencing, metagenomic sequencing, and metabolomics.
RESULTS
The primary compounds in serum were zederone, p-coumaric acid, dehydrocostus lactone, curdione, curcumol. The growth of ectopic lesions in a rat model was effectively inhibited by SL-EZ. In comparison to the control group, the endometriotic rats exhibited a decrease in α-diversity of the gut microbiota, an increase in the Firmicutes/Bacteroidetes ratio, and a reduction in the abundance of Ruminococcaceae. Following SL-EZ intervention, the potential probiotic strains Lactobacillus gasseri and Lactobacillus johnsonii were able to restore the intestinal microenvironment at the species level. The altered metabolites were significantly correlated with Verrucomicrobia, Proteobacteria, and Bacteroidetes. The metabolomic analysis demonstrated significant alterations in intestinal metabolites. And SL-EZ intervention also exerted regulatory effects on various metabolic pathways in gut microbiota, including aminoacyl-tRNA biosynthesis, monobactam biosynthesis, cyanoamino acid metabolism, glycine, serine and threonine metabolism, plant secondary metabolite biosynthesis, and amino acid biosynthesis.
CONCLUSION
The identification of novel treatment formulations for endometriosis was achieved through the utilization of network pharmacology and gut microbiota analyses. Our findings revealed simultaneous alterations in the microbiota within the rat model of endometriosis. The therapeutic efficacy of SL-EZ in treating endometriosis is attributed to its ability to restore the gut microbiota and regulate metabolism. This investigation offers valuable insights into the therapeutic mechanisms of traditional Chinese medicine (TCM) for endometriosis.
Topics: Humans; Rats; Female; Animals; Curcuma; Drugs, Chinese Herbal; Metagenome; Chromatography, Liquid; Endometriosis; Genes, rRNA; Tandem Mass Spectrometry; Metabolomics
PubMed: 38277707
DOI: 10.1016/j.jpba.2024.115970 -
European Journal of Clinical... Apr 2024The combination of ceftazidime-avibactam (CAZ-AVI) and aztreonam (ATM) is used to treat MBL-producing Enterobacterales-related infections. The new combination...
The combination of ceftazidime-avibactam (CAZ-AVI) and aztreonam (ATM) is used to treat MBL-producing Enterobacterales-related infections. The new combination aztreonam-avibactam (AZA) is currently in development. We compared results obtained with the new MIC test strip (MTS) AZA (Liofilchem) with broth microdilution method (BMD) on 41 MBL-producing Enterobacterales from 41 clinical samples. The MTS AZA was also compared to combination testing method using CAZ-AVI and ATM strips. Compared to BMD, categorical agreement (CA) was 100%. Compared with combination testing method, CA was 97.6%. The MTS AZA can be used to determine MICs levels of AZA or CAZ-AVI/ATM combinations.
Topics: Humans; Aztreonam; Anti-Bacterial Agents; Ceftazidime; beta-Lactamases; Drug Combinations; Microbial Sensitivity Tests; Azabicyclo Compounds
PubMed: 38277033
DOI: 10.1007/s10096-024-04766-2 -
Expert Review of Anti-infective Therapy Apr 2024Metallo-beta-lactamases (MBLs) are responsible for resistance to almost all beta-lactam antibiotics. Found predominantly in Gram-negative bacteria, they severely limit... (Review)
Review
INTRODUCTION
Metallo-beta-lactamases (MBLs) are responsible for resistance to almost all beta-lactam antibiotics. Found predominantly in Gram-negative bacteria, they severely limit treatment options. Understanding the epidemiology, risk factors, treatment, and prevention of infections caused by MBL-producing organisms is essential to reduce their burden.
AREAS COVERED
The origins and structure of MBLs are discussed. We describe the mechanisms of action that differentiate MBLs from other beta-lactamases. We discuss the global epidemiology of MBL-producing organisms and their impact on patients' outcomes. By exposing the mechanisms of transmission of MBLs among bacterial populations, we emphasize the importance of infection prevention and control.
EXPERT OPINION
MBLs are spreading globally and challenging the majority of available antibacterial agents. Genotypic tests play an important role in the identification of MBL production. Phenotypic tests are less specific but may be used in low-resource settings, where MBLs are more predominant. Infection prevention and control are critical to reduce the spread of organisms producing MBL in healthcare systems. New combinations such as avibactam-aztreonam and new agents such as cefiderocol have shown promising results for the treatment of infections caused by MBL-producing organisms. New antibiotic and non-antibiotic agents are being developed and may improve the management of infections caused by MBL-producing organisms.
Topics: Humans; beta-Lactamases; Anti-Bacterial Agents; Aztreonam; Gram-Negative Bacteria; Bacteria; Microbial Sensitivity Tests; beta-Lactamase Inhibitors
PubMed: 38275276
DOI: 10.1080/14787210.2024.2311213 -
Journal of Global Antimicrobial... Mar 2024The rapid spread of the New Delhi Metal-β-lactamase-1 (NDM-1) gene in Klebsiella pneumoniae poses a substantial challenge to pediatric therapeutic care. Here, we aimed...
Clone dissemination of IncX3 plasmid carrying bla in ST76 carbapenem resistance Klebsiella pneumoniae and bactericidal efficiency of aztreonam combined with avibactam in vitro and in vivo.
OBJECTIVES
The rapid spread of the New Delhi Metal-β-lactamase-1 (NDM-1) gene in Klebsiella pneumoniae poses a substantial challenge to pediatric therapeutic care. Here, we aimed to characterise the IncX3-type plasmid carrying the bla gene in ST76 carbapenem resistance K. pneumoniae (CRKP) strains and assess the in vitro and in vivo bactericidal efficacy of Aztreonam (ATM) combined with Avibactam (AVI) (ATM+AVI) against CRKP.
METHODS
The broth microdilution method and PCR were used to detect antimicrobial susceptibility and antibiotic resistance genes. Genetic relatedness was determined using Pulsed-Field Gel Electrophoresis (PFGE) and Multilocus Sequence Typing (MLST). The plasmid conjugation assay was used to verify the transmissibility of drug-resistant plasmids. Whole-Genome Sequencing (WGS) was employed to elucidate the genomic attributes of the genes. The Fractional Inhibitory Concentration (FIC) was calculated based on the checkerboard titration assay to determine the antimicrobial effect of ATM+AVI. The time-kill curve assay and a mouse anti-infection model were used to investigate the in vitro and in vivo bactericidal efficiency of ATM+AVI.
RESULTS
Seven bla-producing strains were found to be highly resistant to carbapenems, and they all belonged to the same sequence type (ST76) and were classified into the same PFGE clusters with an 89.1% similarity. The conjugation assay showed that the bla-carrying plasmid was successfully transferred to Escherichia coli 600, resulting in transconjugants with carbapenem antibiotic resistance. A 54-kb IncX3 plasmid (pNDM-XZA88) carried the bla gene located on a Tn125 transposon-like element structure, demonstrating the transferability of resistance genes. Genome comparative analysis revealed that pNDM-XZA88 was highly similar to pCQ17 × 3 and pRor-30818cz and had relatively conserved backbones and variable accessory regions compared to the other four plasmids (pC39-334 kb, pNDM-1-DY1928, pNDM-K725, and pNDM-Z244). The checkerboard titration and time-kill curve assays revealed that the ATM+AVI combination therapy exerted significant bactericidal efficacy against the bla-producing strains in vitro. The ATM+AVI combination also significantly reduced the bacterial burden in a mouse infection model constructed using the bla-producing K. pneumoniae.
CONCLUSION
This study demonstrated the clone dissemination of bla-harboring IncX3 plasmids among the ST76 K. pneumoniae isolated from pediatric patients. Therefore, more attention should be paid to preventing this high-risk clone from harming pediatric patients. Moreover, we deduced that the ATM+AVI combination therapy is an effective strategy for treating bla-producing K. pneumoniae.
Topics: Animals; Mice; Humans; Child; Klebsiella pneumoniae; Aztreonam; Multilocus Sequence Typing; Microbial Sensitivity Tests; Anti-Bacterial Agents; Plasmids; Carbapenem-Resistant Enterobacteriaceae; Escherichia coli; Carbapenems; Azabicyclo Compounds
PubMed: 38272211
DOI: 10.1016/j.jgar.2023.12.031 -
Expert Review of Anti-infective Therapy Apr 2024Carbapenem-resistant Enterobacterales (CRE) due to Metallo-β-lactamase (MBL) production are treated with either polymyxins or the novel combination of... (Meta-Analysis)
Meta-Analysis Review
Ceftazidime-avibactam and aztreonam combination for Carbapenem-resistant Enterobacterales bloodstream infections with presumed production: a systematic review and meta-analysis.
INTRODUCTION
Carbapenem-resistant Enterobacterales (CRE) due to Metallo-β-lactamase (MBL) production are treated with either polymyxins or the novel combination of ceftazidime-avibactam and aztreonam (AA). This study aims to evaluate the 30-day mortality of AA in patients with BSI caused by MBL-CRE infections.
METHODOLOGY
In this systematic review and meta-analysis, all articles up to June 2023 were screened using search terms like 'CRE', 'MBL', 'AA' and 'polymyxins'. The risk ratio for AA vs polymyxins was pooled using a random-effect model, and the results were represented by a point estimate with a 95% confidence interval.
RESULTS
After removing the duplicates, the titles and abstracts of 455 articles were screened, followed by a full-text screening of 50 articles. A total of 24 articles were included for systematic review, and four comparative studies were included in the meta-analysis. All four studies had a moderate or serious risk of bias. The pooled risk ratio for 30-day mortality for AA vs. polymyxins was 0.51 (95%CI: 0.34-0.76), < 0.001. There was no significant heterogeneity.
CONCLUSION
The meta-analysis from studies with a high risk of bias shows that AA is associated with lesser 30-day mortality when compared to polymyxins in patients with MBL-producing CRE BSI. Registration with PROSPERO- CRD42023433608.
Topics: Humans; Aztreonam; Sepsis; Drug Combinations; Polymyxins; beta-Lactamases; Carbapenems; Anti-Bacterial Agents; Microbial Sensitivity Tests; Azabicyclo Compounds; Ceftazidime
PubMed: 38258529
DOI: 10.1080/14787210.2024.2307912 -
European Journal of Clinical... Apr 2024A series of iterative population pharmacokinetic (PK) modeling and probability of target attainment (PTA) analyses based on emerging data supported dose selection for...
PURPOSE
A series of iterative population pharmacokinetic (PK) modeling and probability of target attainment (PTA) analyses based on emerging data supported dose selection for aztreonam-avibactam, an investigational combination antibiotic for serious Gram-negative bacterial infections.
METHODS
Two iterations of PK models built from avibactam data in infected patients and aztreonam data in healthy subjects with "patient-like" assumptions were used in joint PTA analyses (primary target: aztreonam 60% fT > 8 mg/L, avibactam 50% fT > 2.5 mg/L) exploring patient variability, infusion durations, and adjustments for moderate (estimated creatinine clearance [CrCL] > 30 to ≤ 50 mL/min) and severe renal impairment (> 15 to ≤ 30 mL/min). Achievement of > 90% joint PTA and the impact of differential renal clearance were considerations in dose selection.
RESULTS
Iteration 1 simulations for Phase I/IIa dose selection/modification demonstrated that 3-h and continuous infusions provide comparable PTA; avibactam dose drives joint PTA within clinically relevant exposure targets; and loading doses support more rapid joint target attainment. An aztreonam/avibactam 500/137 mg 30-min loading dose and 1500/410 mg 3-h maintenance infusions q6h were selected for further evaluation. Iteration 2 simulations using expanded PK models supported an alteration to the regimen (500/167 mg loading; 1500/500 mg q6h maintenance 3-h infusions for CrCL > 50 mL/min) and selection of doses for renal impairment for Phase IIa/III clinical studies.
CONCLUSION
A loading dose plus 3-h maintenance infusions of aztreonam-avibactam in a 3:1 fixed ratio q6h optimizes joint PTA. These analyses supported dose selection for the aztreonam-avibactam Phase III clinical program.
CLINICAL TRIAL REGISTRATION
NCT01689207; NCT02655419; NCT03329092; NCT03580044.
Topics: Humans; Anti-Bacterial Agents; Azabicyclo Compounds; Aztreonam; Drug Combinations; Microbial Sensitivity Tests
PubMed: 38252170
DOI: 10.1007/s00228-023-03609-x -
Indian Journal of Medical Microbiology 2024The choice of antibiotics for treatment of Carbapenem-Resistant Enterobacterales (CRE) is increasing becoming limited due to co-expression of Metallo-beta-lactamases...
PURPOSE
The choice of antibiotics for treatment of Carbapenem-Resistant Enterobacterales (CRE) is increasing becoming limited due to co-expression of Metallo-beta-lactamases (MBL) along with other carbapenemases in these isolates. The study aimed to investigate the occurrence of CRE and to determine the in-vitro synergy and clinical outcomes of Ceftazidime-Avibactam and Aztreonam combination in CRE infections in adult Intensive Care Units (ICUs).
METHODS
79 CRE isolates recovered from adult ICUs during January to March 2023 were tested by O.K.N.V.I. RESIST-5, a lateral flow multiplex assay for rapid detection of OXA-48-like, NDM, IMP, VIM, and KPC carbapenemases. Ceftazidime-Avibactam MIC was determined by microbroth dilution method and in vitro synergy between Ceftazidime-Avibactam and Aztreonam was assessed by Modified E-test/disc diffusion method for these isolates.
RESULTS
The study revealed 7.5 % occurrence of CRE in our hospital, with high occurrence of NDM (n = 42, 53.1 %) and OXA-48-like (n = 63, 79.7 %) carbapenemase. Production of more than one type of carbapenemases was found in 44 isolates. A total of 57 isolates (72 %) had Ceftazidime-Avibactam resistance and 44 of them displayed Ceftazidime-Avibactam and Aztreonam in-vitro synergy. Successful clinical outcome was observed in two patients who received Ceftazidime-Avibactam and Aztreonam combination therapy for 7 days or more.
CONCLUSIONS
Despite the preponderance of Ceftazidime-Avibactam resistant CRE expressing NDM and OXA-48-like carbapenemase in our hospital, 77.2 % of them displayed in-vitro synergy of Ceftazidime-Avibactam with Aztreonam. It emphasizes the potential therapeutic utility of this combination in CRE strains showing coproduction of MBL and serine carbapenemases. Greater therapeutic potential of Ceftazidime-Avibactam and Aztreonam combination was observed with extended duration of therapy. However, further clinical evidence is needed to establish the efficacy of this combination and consider other factors that influence treatment outcomes.
Topics: Adult; Humans; Aztreonam; Ceftazidime; Anti-Bacterial Agents; Drug Combinations; beta-Lactamases; Carbapenems; Microbial Sensitivity Tests; Azabicyclo Compounds
PubMed: 38246242
DOI: 10.1016/j.ijmmb.2024.100530 -
The Journal of Surgical Research Apr 2024Diverticulitis and appendicitis are common emergency general surgical conditions. Both can be treated with antibiotics alone; however, no antibiotic regimen has been... (Review)
Review
INTRODUCTION
Diverticulitis and appendicitis are common emergency general surgical conditions. Both can be treated with antibiotics alone; however, no antibiotic regimen has been identified as superior to others. In this study, we review different antibiotic regimens and their rates of failure.
METHODS
Retrospective cohort study of patients treated empirically with antibiotics for diverticulitis or appendicitis from January 1, 2018, to December 31, 2020, at an independent academic hospital in the Midwest.
RESULTS
A total of 587 (appendicitis, n = 43; diverticulitis, n = 544) patients were included in the cohort. They were equally male (49%) and female (51%) with a median age of 59 y. Three major antibiotic classes were compared: cephalosporin + metronidazole (C + M), penicillins, and quinolone + metronidazole. Appendicitis patients were more likely to receive C + M for empiric treatment (73%, P < 0.001), while diverticulitis patients were more likely to receive quinolone + metronidazole (45%, P < 0.001). Patients empirically treated with antibiotics for appendicitis were more likely than those treated for diverticulitis to require additional antibiotics or procedure within 90 d (33% versus 13%, respectively; P = 0.005). Empiric treatment with C + M for diverticulitis was more likely to be associated with the need for additional antibiotics or procedures within 90 d than treatment with other regimens (P = 0.003). Choice of antibiotic for empiric treatment did not correlate with death at 90 d for appendicitis or diverticulitis. Diverticulitis patients who were initially treated as inpatients and were prescribed C + M at hospital discharge had a higher rate of death than those who were prescribed the other antibiotics (P = 0.04).
CONCLUSIONS
Empiric antibiotic treatment of appendicitis is more likely to be associated with additional antibiotics or procedure when compared with diverticulitis; however, antibiotic choice did not correlate with any of the other outcomes. Empiric treatment with a C + M for diverticulitis was more likely to be correlated with the need for additional antibiotics or procedure within 90 d.
Topics: Humans; Male; Female; Anti-Bacterial Agents; Metronidazole; Appendicitis; Retrospective Studies; Cephalosporins; Diverticulitis; Appendectomy; Monobactams; Quinolones; Treatment Outcome; Acute Disease
PubMed: 38232581
DOI: 10.1016/j.jss.2023.12.011 -
Microbial Drug Resistance (Larchmont,... Mar 2024Multidrug-resistant is a serious concern worldwide. Resistance to β-lactam antibiotics occurs through mutations in penicillin-binding proteins (PBPs), acquisition of...
Multidrug-resistant is a serious concern worldwide. Resistance to β-lactam antibiotics occurs through mutations in penicillin-binding proteins (PBPs), acquisition of β-lactamases, and alteration of antibiotic penetration. Mosaic structures of , which encodes PBP2, play a major role in resistance to β-lactams, especially cephalosporins. Ceftriaxone (CRO) is recognized as the only satisfiable antibiotic for the treatment of gonococcal infections; however, CRO-resistant isolates have emerged in the community. Here, we examined the affinity of β-lactam antibiotics for recombinant PBP2 in a competition assay using fluorescence-labeled penicillin. We found no or little difference in the affinities of penicillins and meropenem (MEM) for PBP2 from cefixime (CFM)-reduced-susceptible strain and cephalosporin-resistant strain. However, the affinity of cephalosporins, including CRO, for PBP2 from the cephalosporin-resistant strain was markedly lower than that for PBP2 from the CFM-reduced-susceptible-resistant strain. Notably, piperacillin (PIP) showed almost the same affinity for PBP2 from penicillin-susceptible, CFM-reduced-susceptible, and cephalosporin (including CRO)-resistant strains. Thus, PIP/tazobactam and MEM are candidate antibiotics for the treatment of CRO-resistant/multidrug-resistant .
Topics: Humans; Ceftriaxone; Cephalosporins; Cefixime; Anti-Bacterial Agents; Penicillin-Binding Proteins; Neisseria gonorrhoeae; beta Lactam Antibiotics; Alleles; Microbial Sensitivity Tests; Gonorrhea; Monobactams; Penicillins
PubMed: 38215246
DOI: 10.1089/mdr.2023.0256