Showing papers on "Aztreonam published in 2020"
TL;DR: Observed AEs were consistent with the known safety profile of aztreonam monotherapy, with no new safety concerns identified, and data support selection of the azTreonam/avibactam 500/167 mg loading dose and 1500/500mg maintenance dose q6h regimen, in patients with creatinine clearance >50 mL/min, for the Phase 3 development programme.
Abstract: Objectives To investigate pharmacokinetics (PK) and safety (primary objectives) and efficacy (secondary objective) of the investigational monobactam/β-lactamase inhibitor combination aztreonam/avibactam in patients with complicated intra-abdominal infection (cIAI). Methods This Phase 2a open-label, multicentre study (NCT02655419; EudraCT 2015-002726-39) enrolled adults with cIAI into sequential cohorts for 5-14 days treatment. Cohort 1 patients received an aztreonam/avibactam loading dose of 500/137 mg (30 min infusion), followed by maintenance doses of 1500/410 mg (3 h infusions) q6h; Cohort 2 received 500/167 mg (30 min infusion), followed by 1500/500 mg (3 h infusions) q6h. Cohort 3 was an extension of exposure at the higher dose regimen. Doses were adjusted for creatinine clearance of 31-50 mL/min (Cohorts 2 + 3). All patients received IV metronidazole 500 mg q8h. PK, safety and efficacy were assessed. Results Thirty-four patients (Cohort 1, n = 16; Cohorts 2 + 3, n = 18) comprised the modified ITT (MITT) population. Mean exposures of aztreonam and avibactam in Cohorts 2 + 3 were consistent with those predicted to achieve joint PK/pharmacodynamic target attainment in >90% patients. Adverse events (AEs) were similar between cohorts. The most common AEs were hepatic enzyme increases [n = 9 (26.5%)] and diarrhoea [n = 5 (14.7%)]. Clinical cure rates at the test-of-cure visit overall were 20/34 (58.8%) (MITT) and 14/23 (60.9%) (microbiological-MITT population). Conclusions Observed AEs were consistent with the known safety profile of aztreonam monotherapy, with no new safety concerns identified. These data support selection of the aztreonam/avibactam 500/167 mg (30 min infusion) loading dose and 1500/500 mg (3 h infusions) maintenance dose q6h regimen, in patients with creatinine clearance >50 mL/min, for the Phase 3 development programme.
47 citations
TL;DR: Recognition of the molecular basis of carbapenem resistance allowed for successful treatment by combining CAZ-AVI and ATM and antimicrobial synergy testing and therapeutic drug monitoring allowed for assessment of treatment adequacy.
Abstract: In an infection with an Enterobacter sp. isolate producing Klebsiella pneumoniae Carbapenemase-4 and New Delhi Metallo-β-Lactamase-1 in the United States, recognition of the molecular basis of carbapenem resistance allowed for successful treatment by combining ceftazidime-avibactam and aztreonam. Antimicrobial synergy testing and therapeutic drug monitoring assessed treatment adequacy.
44 citations
TL;DR: Cefiderocol treatment for 14 weeks plus bone implantation resulted in apparent cure and avoided amputation and neurological side effects in the form of circumoral paresthesia with polymyxin B and asymptomatic elevation of transaminases with aztreonam (used in combination with ceftazidime-avibactam).
Abstract: We report a 15 year-old Nigerian adolescent male with chronic osteomyelitis caused by an extensively drug-resistant (XDR) Pseudomonas aeruginosa strain of sequence type 773 (ST773) carrying bla NDM-1 and an extended spectrum β-lactamase (ESBL)-producing Klebsiella pneumoniae strain. The patient developed neurological side effects in the form of circumoral paresthesia with polymyxin B and asymptomatic elevation of transaminases with aztreonam (used in combination with ceftazidime-avibactam). Cefiderocol treatment for 14 weeks plus bone implantation resulted in apparent cure and avoided amputation.
35 citations
TL;DR: It is shown here that elevated MICs of ATM-AVI among MBL-producing E. coli isolates resulted from a combination of different features, including modification of PBP3 protein sequence through specific amino acid insertions and production of CMY-type enzymes, particularly,CMY-42.
Abstract: Metallo-β-lactamase (MBL)-producing Escherichia coli isolates resistant to the newly developed β-lactam/β-lactamase inhibitor drug combination aztreonam-avibactam (ATM-AVI) have been reported. Here, we analyzed a series of 118 clinical MBL-producing E. coli isolates of various geographical origins for susceptibility to ATM-AVI. The nature of the PBP3 protein sequence and the occurrence of bla CMY genes for susceptibility to ATM-AVI were investigated. We showed here that elevated MICs of ATM-AVI among MBL-producing E. coli isolates resulted from a combination of different features, including modification of PBP3 protein sequence through specific amino acid insertions and production of CMY-type enzymes, particularly, CMY-42. We showed here that those insertions identified in the PBP3 sequence are not considered the unique basis of resistance to ATM-AVI, but they significantly contribute to it.
32 citations
TL;DR: Pseudomonas isolates were most highly resistant to imipenem, followed by trimethoprim-sulfamethoxazole, which suggests that antibiotic resistance of Pseudomona spp.
Abstract: Psychrotrophic bacteria in raw milk are most well known for their spoilage potential and the economic losses they cause to the dairy industry. Food-related psychrotrophic bacteria are increasingly reported to have antibiotic resistance features. The aim of this study was to evaluate the resistance patterns of Pseudomonas spp. isolated from bulk-tank milk. In total, we investigated the antibiotic susceptibility profiles of 86 Pseudomonas spp. isolates from raw milk. All strains were tested against 15 antimicrobial agents. Pseudomonas isolates were most highly resistant to imipenem (95.3%), followed by trimethoprim-sulfamethoxazole (69.8%), aztreonam (60.5%), chloramphenicol (45.3%), and meropenem (27.9%). Their multiple antibiotic resistance (MAR) index values ranged from 0.0 to 0.8. Whole-genome sequencing revealed the presence of intrinsic resistance determinants, such as BcI, ampC-09, blaCTX-M, oprD, sul1, dfrE, catA1, catB3, catI, floR, and cmlV. Moreover, resistance-nodulation-cell division (RND) and ATP-binding cassette (ABC) antibiotic efflux pumps were also found. This study provides further knowledge of the antibiotic resistance patterns of Pseudomonas spp. in milk, which may advance our understanding of resistance in Pseudomonas and suggests that antibiotic resistance of Pseudomonas spp. in raw milk should be a concern.
32 citations
TL;DR: The study suggested the likelihood of aztreonam/avibactam resistance among MBL- and AmpC-co-producing strains and clinical practice should beware of the possibility of the emerging resistance.
Abstract: Objectives To examine the in vitro selection of aztreonam/avibactam resistance among MBL-producing Klebsiella pneumoniae and to understand the mechanism of increased resistance. Methods The MICs of aztreonam were determined with and without avibactam (4 mg/L) using a broth microdilution method. Single-step and multi-step mutant selection was conducted on five MBL-producing K. pneumoniae strains, including two dual carbapenemase producers. Genomic sequencing and gene cloning were performed to investigate the mechanism of increased resistance. Results We examined the MICs for 68 MBL-producing K. pneumoniae isolates, including 13 dual carbapenemase producers. Compared with aztreonam alone, the addition of avibactam (4 mg/L) reduced the MICs for all isolates by >128-fold, with MIC50 and MIC90 values of 0.25 and 1 mg/L, respectively. One NDM-1-, OXA-48-, CTX-M-15- and CMY-16-positive ST101 K. pneumoniae strain was selected to be resistant to aztreonam/avibactam, with a >16-fold increase in MIC (>128 mg/L). WGS revealed that the resistant mutants lost the blaNDM-1 gene, but acquired amino acid substitutions in CMY-16 (Tyr150Ser and Asn346His). Construction of blaCMY-16 mutants confirmed that the substitutions (Tyr150Ser and Asn346His) were primarily responsible for the decreased susceptibility to aztreonam/avibactam. In addition, transfer of blaCMY-16 mutant (Tyr150Ser and Asn346His) plasmid constructs into certain clinical carbapenemase-producing isolates demonstrated >64-fold increased MICs of aztreonam/avibactam and aztreonam/avibactam/ceftazidime. Conclusions Aztreonam in combination with avibactam showed potent in vitro activity against MBL-producing K. pneumoniae. However, our study suggested the likelihood of aztreonam/avibactam resistance among MBL- and AmpC-co-producing strains and clinical practice should beware of the possibility of the emerging resistance.
31 citations
TL;DR: Simultaneous administration of aztreonam 8 g/day given as a continuous or 2 h infusion with ceftazidime/avibactam resulted in complete bacterial eradication and resistance suppression and warrants further study in Phase 1 clinical trials.
Abstract: Background MBL-producing strains of Enterobacteriaceae are a major public health concern. We sought to define optimal combination regimens of ceftazidime/avibactam with aztreonam in a hollow-fibre infection model (HFIM) of MBL-producing strains of Escherichia coli and Klebsiella pneumoniae. Methods E. coli ARLG-1013 (blaNDM-1, blaCTX-M, blaCMY, blaTEM) and K. pneumoniae ARLG-1002 (blaNDM-1, blaCTXM-15, blaDHA, blaSHV, blaTEM) were studied in the HFIM using simulated human dosing regimens of ceftazidime/avibactam and aztreonam. Experiments were designed to evaluate the effect of staggered versus simultaneous administration, infusion duration and aztreonam daily dose (6 g/day versus 8 g/day) on bacterial killing and resistance suppression. Prospective validation experiments for the most active combination regimens were performed in triplicate to ensure reproducibility. Results Staggered administration of the combination (ceftazidime/avibactam followed by aztreonam) was found to be inferior to simultaneous administration. Longer infusion durations (2 h and continuous infusion) also resulted in enhanced bacterial killing relative to 30 min infusions. The rate of killing was more pronounced with 8 g/day versus 6 g/day aztreonam combination regimens for both tested strains. In the prospective validation experiments, ceftazidime/avibactam with aztreonam dosed every 8 and 6 h, respectively (ceftazidime/avibactam 2/0.5 g every 8 h + aztreonam 2 g every 6 h), or ceftazidime/avibactam with aztreonam as continuous infusions resulted in maximal bacterial killing and resistance suppression over 7 days. Conclusions Simultaneous administration of aztreonam 8 g/day given as a continuous or 2 h infusion with ceftazidime/avibactam resulted in complete bacterial eradication and resistance suppression. Further study of this combination is needed with additional MBL-producing Gram-negative pathogens. The safety of this double β-lactam strategy also warrants further study in Phase 1 clinical trials.
30 citations
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27 citations
TL;DR: The susceptibility of NDM-producing isolates to 32 currently available antibiotics was determined using reference broth microdilution and the in vitro activity of 3 combination agents that are not yet available was explored.
Abstract: The treatment of infections caused by carbapenem-resistant Enterobacterales, especially New Delhi metallo-β-lactamase (NDM)-producing bacteria, is challenging. Although less common in the United States than some other carbapenemase producers, NDM-producing bacteria are a public health threat due to the limited treatment options available. Here, we report on the antibiotic susceptibility of 275 contemporary NDM-producing Enterobacterales collected from 30 U.S. states through the Centers for Disease Control and Prevention's Antibiotic Resistance Laboratory Network. The aims of the study were to determine the susceptibility of these isolates to 32 currently available antibiotics using reference broth microdilution and to explore the in vitro activity of 3 combination agents that are not yet available. Categorical interpretations were determined using Clinical and Laboratory Standards Institute (CLSI) interpretive criteria. For agents without CLSI criteria, Food and Drug Administration (FDA) interpretive criteria were used. The percentage of susceptible isolates did not exceed 90% for any of the FDA-approved antibiotics tested. The antibiotics with breakpoints that had the highest in vitro activity were tigecycline (86.5% susceptible), eravacycline (66.2% susceptible), and omadacycline (59.6% susceptible); 18.2% of isolates were susceptible to aztreonam. All NDM-producing isolates tested were multidrug resistant, and 116 isolates were extensively drug resistant (42.2%); 207 (75.3%) isolates displayed difficult-to-treat resistance. The difficulty in treating infections caused by NDM-producing Enterobacterales highlights the need for containment and prevention efforts to keep these infections from becoming more common.
TL;DR: In the context of increasing CR-PSA and the genetic diversity of resistance mechanisms, new combinations and stewardship strategies may need to be explored in the face of increasingly difficult to treat pathogens.
Abstract: Objectives Carbapenem-resistant Pseudomonas aeruginosa (CR-PSA) imposes great limitations on empirical therapeutic choices, which are further complicated by metallo-β-lactamase production. This study evaluated in vitro antimicrobial synergy of ceftolozane/tazobactam in combination with aztreonam and fosfomycin against MDR PSA. Methods MICs were determined by broth microdilution and gradient strips. The effect of ceftolozane/tazobactam+aztreonam and ceftolozane/tazobactam+fosfomycin combinations were tested against 27 MDR PSA isolates carrying blaSPM-1 (n = 13), blaIMP (n = 4), blaVIM (n = 3), blaGES-1 (n = 2) and blaCTX-M-like (n = 2), and 3 isolates with no acquired β-lactamase production detected by gradient diffusion strip crossing (GDSC). Six genetically unrelated SPM-1-producing isolates were also evaluated by time-kill analysis (TKA). Results All CR-PSA isolates harbouring blaSPM-1, blaGES-1 and blaIMP-1 were categorized as resistant to ceftolozane/tazobactam, meropenem and fosfomycin, with 70% being susceptible to aztreonam. Synergism for ceftolozane/tazobactam+fosfomycin and ceftolozane/tazobactam+aztreonam combinations was observed for 88.9% (24/27) and 18.5% (5/27) of the isolates by GDSC, respectively. A 3- to 9-fold reduction in ceftolozane/tazobactam MICs was observed, depending on the combination. Ceftolozane/tazobactam+fosfomycin was synergistic by TKA against one of six SPM-1-producing isolates, with additional non-synergistic bacterial density reduction for another isolate. Aztreonam peak concentrations alone demonstrated a ≥3 log10 cfu/mL reduction against all six isolates, but all strains were within the susceptible range for the drug. No antagonism was observed. Conclusions In the context of increasing CR-PSA and the genetic diversity of resistance mechanisms, new combinations and stewardship strategies may need to be explored in the face of increasingly difficult to treat pathogens.
TL;DR: Murepavadin demonstrated the highest activity on a per-weight basis and may therefore become a valuable addition to the currently available antibiotics for treatment of respiratory infection in people with CF.
Abstract: The objective was to determine the in vitro antimicrobial susceptibility of Pseudomonas aeruginosa isolates cultured from cystic fibrosis (CF) patients and explore associations between strain sequence type and susceptibility. Fourteen antibiotics and antibiotic combinations, including the novel antibacterial peptide murepavadin, were tested for activity against 414 Pseudomonas aeruginosa isolates cultured from respiratory samples of CF patients. The complete genomes of the isolates were sequenced, and minimum spanning trees were constructed based on the sequence types (STs). Percentages of resistance according to CLSI 2019 breakpoints were as follows: cefepime, 14%; ceftazidime, 11%; ceftazidime-avibactam, 7%; ceftolozane-tazobactam, 3%; piperacillin-tazobactam, 12%; meropenem, 18%; imipenem, 32%; aztreonam, 23%; ciprofloxacin, 30%; gentamicin, 30%; tobramycin, 12%; amikacin, 18%; and colistin, 4%. Murepavadin MIC50 and MIC90 were 0.12 mg/liter and 2 mg/liter, respectively. There were no apparent clonal clusters associated with resistance, but higher MICs did appear to occur more often in STs with multiple isolates than in single ST isolates. In general, the CF isolates showed a wide genetic distribution. P. aeruginosa CF isolates exhibited the lowest resistance rates against ceftolozane-tazobactam, ceftazidime-avibactam, and colistin. Murepavadin demonstrated the highest activity on a per-weight basis and may therefore become a valuable addition to the currently available antibiotics for treatment of respiratory infection in people with CF.
TL;DR: In patients with such hypersensitivity who need these alternative β-lactams, pretreatment skin tests are advisable because of the possibility of coexisting sensitivities or, much less frequently, of a sensitivity to an antigenic determinant of the common β- lactam ring.
TL;DR: The prevalence of fluoroquinolone and cephalosporin resistance among common UTI-causing gram-negative bacteria highlights the growing challenge of successfully treating community-onsetUTIs.
Abstract: Background Urinary tract infections (UTIs) are among the most common bacterial infections in clinical practice. This RESOURCE (pathogen distribution and antibiotic RESistance prOfile of key Gram-negative bacteria caUsing community-onsEt URinary traCt) study aimed to determine the antimicrobial resistance profile of Gram-negative bacteria isolated from outpatient urine samples collected across the Russian Federation. Methods A total of 96 781 urine samples were collected from 520 cities in the Russian Federation between 01 January 1 and 31 December 2017. Antibiotic susceptibility was performed using semi-automated analysers. The mean age of the study population was 40.9 years; 80.2% were female and 19.8% were male. Results Of the uropathogens that were isolated, 64.2% were Gram-negative bacteria. Among these, Escherichia coli (E. coli) was the most common (49.1%) followed by Klebsiella pneumoniae (9.5%), Proteus mirabilis (2.9%), Pseudomonas aeruginosa (1.7%), and Enterobacter spp. (1.0%). Of the antibiotics that were tested, 50% of the isolated E. coli strains were resistant to ampicillin, 30.3% to co-trimoxazole, 26.2% to aztreonam, 28.8% to levofloxacin, and 21% to cefuroxime. Conversely, E. coli was highly susceptible to imipenem (0.7% resistant strains isolated), amikacin (0.9%), nitrofurantoin (4.5%), and fosfomycin (1.2%). The most active antimicrobials against Klebsiella pneumoniae were imipenem (6.8% resistant strains) and colistin (0.5%), while piperacillin/tazobactam (4.2%), cefoperazone/sulbactam (3.1%) and imipenem (0%) were the most active agents against Proteus mirabilis. The antimicrobials showing the highest activity against Pseudomonas aeruginosa were colistin (10.7% resistant strains) and aztreonam (0%), while piperacillin/tazobactam (7.1%) and cefoperazone/sulbactam (2.3%) showed the highest activity against Enterobacter spp. Conclusion The prevalence of fluoroquinolone and cephalosporin resistance among common UTI-causing Gram-negative bacteria highlights the growing challenge of successfully treating community-onset UTIs.
TL;DR: Findings of the present study showed a rising trend of resistance to the drugs of choice for the treatment of Salmonella infections, i.e. ampicillin, chloramphenicol and trimethoprim-sulfamethoxazole in Iran.
Abstract: The present study was conducted to investigate the antimicrobial susceptibility profiles of Salmonella serotypes, especially fluoroquinolone-resistant strains, recovered from clinical samples in Iran. A full electronic search using related keywords was conducted in Persian and English languages in ISI Web of Knowledge, PubMed, Scopus, Google Scholar and the Scientific Information Database (SID) search engines to find papers published between 1983 and 1 July 2019. According to the inclusion and exclusion criteria, 46 eligible articles were selected for the final analysis out of the initial 13,186 studies retrieved. The pooled prevalence of quinolone-resistant Salmonella serotypes in clinical specimens in Iran was 2.9% to ciprofloxacin and 48.1% to nalidixic acid. Additional data on antibiotic resistance was as follows: 54.3% to tetracycline, 50.6% to ceftizoxime, 50.2% to streptomycin, 37.9% to ampicillin, 36.5% to kanamycin, 33.5% to trimethoprim-sulfamethoxazole, 27.2% to chloramphenicol, 19.1% to cephalothin, 8.8% to ceftriaxone, 7.6% to cefotaxime, 7.4% to aztreonam, 7.2% to gentamicin, 7% to cefepime, 6.8% to ceftazidime, 5.8% to cefixime, 2.7% to imipenem and 2.2% to meropenem. Findings of the present study showed a rising trend of resistance to the drugs of choice for the treatment of Salmonella infections, i.e. ampicillin, chloramphenicol and trimethoprim-sulfamethoxazole in Iran. However, ciprofloxacin, third-generation cephalosporins and carbapenems are still effective antibiotics especially against multi-drug resistant strains in Iran.
TL;DR: Aztreonam-avibactam is the most promising BLI-combination against multidrug resistant Stenotrophomonas maltophilia as discussed by the authors, however, it has not been explored molecular mechanisms for reduced susceptibility to these combinations.
Abstract: The intrinsic L1 metallo- and L2 serine-β-lactamases in Stenotrophomonas maltophilia make it naturally multidrug resistant and difficult to treat. There is a need to identify novel treatment strategies for this pathogen, especially against isolates resistant to first line agents. Aztreonam in combination with avibactam has demonstrated potential, although data on other aztreonam-β-lactamase inhibitor (BLI) combinations are lacking. Additionally, molecular mechanisms for reduced susceptibility to these combinations have not been explored. The objectives of this study were to evaluate and compare the in vitro activity and understand the mechanisms of resistance to aztreonam in combination with avibactam, clavulanate, relebactam, and vaborbactam against S. maltophilia. A panel of 47 clinical S. maltophilia strains non-susceptible to levofloxacin and/or trimethoprim-sulfamethoxazole were tested against each aztreonam-BLI combination via broth microdilution and 6 isolates were then evaluated in time-kill analyses. Three isolates with varying aztreonam-BLI MICs were subjected to whole-genome sequencing and quantitative reverse transcriptase polymerase chain reaction. Avibactam restored aztreonam susceptibility in 98% of aztreonam-resistant isolates, compared to 61%, 71%, and 15% with clavulanate, relebactam, and vaborbactam, respectively. The addition of avibactam to aztreonam resulted in a ≥2 log10 CFU/mL decrease at 24 hours vs. aztreonam alone against 5/6 isolates compared to 1/6 with clavulanate, 4/6 with relebactam, and 2/6 with vaborbactam. Molecular analyses revealed that decreased susceptibility to aztreonam-avibactam was associated with increased expression of genes encoding for L1, L2, and the efflux pump smeABC. Aztreonam-avibactam is the most promising BLI-combination against multidrug resistant S. maltophilia. Decreased susceptibility may be due to the combination of overexpressed β-lactamases and efflux pumps. Further studies evaluating this combination against S. maltophilia are warranted.
TL;DR: The data obtained are relevant, since the bacteria detected are on the priority pathogens list from the World Health Organization and hospital sewage could be released untreated into the municipal collection system, which may favor the spread of resistance.
Abstract: Multidrug resistance mediated by β-lactamase in Gram-negative bacilli is a serious public health problem. Sewers are considered reservoirs of multiresistant bacteria due to presence of antibiotics that select them and favor their dissemination. The present study evaluated the antibiotic resistance profile and β-lactamases production in Gram-negative bacilli isolates from hospital sewage and urban wastewater treatment plants (UWWTP) in Brazil. Bacteria were isolated and identified with biochemical tests. Antibiotic susceptibility testing was performed by the disk-diffusion method and detection of extended-spectrum β-lactamase and carbapenemases by enzymatic inhibitor and conventional PCR. Differences in resistance to amoxicillin clavulanic, aztreonam, cefepime, and cefotaxime were observed in hospital sewage compared with urban sewage (p < 0.05). The multidrug-resistant phenotype was observed in 33.3% of hospital sewage isolates (p = 0.0025). β-lactamases genes were found in 35.6% of isolates, with the most frequent being blaKPC and blaTEM (17.8%), and blaSHV and blaCTX-M (13.3% and 8.9%, respectively). The data obtained are relevant, since the bacteria detected are on the priority pathogens list from the World Health Organization and hospital sewage could be released untreated into the municipal collection system, which may favor the spread of resistance. Changes in hospital sewage discharge practices, as well as additional technologies regarding effluent disinfection in the UWWTP, can prevent the spread of these bacteria into the environment and negative impact on water resources.
TL;DR: Of the currently available drugs: colistin, tigecycline and ceftazidime-avibactam co-administered with aztreonam appear to be the most effective to treat CRE infections, however, the presence of non-clonal CRE isolates, in which avibactsam does not lower the aztrexam MIC below the clinical breakpoint, is a notable concern.
TL;DR: Dilutional in vitro models may be superior to hollow-fibre systems in terms of cost-effectiveness, biofilm formation and modelled drug concentrations and their close alignment with animal models are shown.
Abstract: 70% would seem appropriate. This is longer than the Gramnegative fT.MIC targets for cephalosporins of 30%–40% 7 and for carbapenems of 20%–35% and more similar to that for penicillins of 30%–60%. All the above data show the robustness of dilutional in vitro models in defining pharmacodynamic target sizes and their close alignment with animal models. Previous concerns about washout have also been shown to be baseless and indeed dilutional models may be superior to hollow-fibre systems in terms of cost-effectiveness, biofilm formation and modelled drug concentrations.
TL;DR: In the last decades, there was an important paucity of agents for adequately treating infections due to metallo-β-lactamases-producing Gram-negative bacteria (MBL-GNB).
Abstract: In the last decades, there was an important paucity of agents for adequately treating infections due to metallo-β-lactamases-producing Gram-negative bacteria (MBL-GNB). Cefiderocol, a novel siderophore cephalosporin showing in vitro activity against MBL-GNB, has been recently marketed, and a combination of aztreonam and ceftazidime/avibactam has shown a possible favorable effect on survival of patients with severe MBL-GNB infections in observational studies. Other agents showing in vitro activity against MBL-GNB are currently in clinical development (e.g., cefepime/taniborbactam, LYS228, cefepime/zidebactam) that could be an important addition to our future armamentarium for severe MBL-GNB infections. Nonetheless, we should not discontinue our efforts to optimize the use of non-β-lactams agents, since they could remain an essential last-resort or alternative option in selected cases.
TL;DR: A formulation of Fmoc-F with the Gram-negative specific antibiotic aztreonam (AZT) produced a synergistic effect and higher efficacy against P. aeruginosa due to the increased FmOC-F permeability by AZT through the bacterial membrane, which could be an effective strategy for the better management of bacterial wound infections.
Abstract: Recently, fluorenylmethyloxycarbonyl (Fmoc) conjugated amino acids (Fmoc-AA), especially Fmoc-phenylalanine (Fmoc-F), have been discovered to have antimicrobial properties specific to Gram-positive bacteria including MRSA. Their weak antibacterial activity against Gram-negative bacteria is due to their inability to cross the bacterial membrane. Here in order to increase the antibacterial spectrum of Fmoc-F, we prepared a formulation of Fmoc-F with the Gram-negative specific antibiotic aztreonam (AZT). This formulation displayed antibacterial activity against both Gram-positive and Gram-negative bacteria and significantly reduced the bacterial load in a mouse wound infection model. The combination produced a synergistic effect and higher efficacy against P. aeruginosa due to the increased Fmoc-F permeability by AZT through the bacterial membrane. This combinatorial approach could be an effective strategy for other Fmoc-AA having a Gram-positive specific antibacterial effect for the better management of bacterial wound infections.
TL;DR: The combined use of aztreonam-avibactam is highly potent against MBL-Enterobacteriaceae and may serve as a new candidate for the treatment of MBLs caused infections in China.
TL;DR: Cefepime/zidebactam demonstrated potent activity, with all isolates inhibited at ≤1 mg/L, and Comparator antibiotics including ceftazidime/avibactam and imipenem/relebactsam showed limited activities.
Abstract: Background Recent reports reveal the emergence of Escherichia coli isolates harbouring a novel resistance mechanism based on four-amino-acid inserts in PBP3. These organisms concomitantly expressed ESBLs or/and serine-/metallo-carbapenemases and were phenotypically detected by elevated aztreonam/avibactam MICs. Objectives The in vitro activities of the investigational antibiotic cefepime/zidebactam and approved antibiotics (ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/relebactam and others) were determined against E. coli isolates harbouring four-amino-acid inserts in PBP3. Methods Whole-genome sequenced E. coli isolates (n = 89) collected from a large tertiary care hospital in Southern India (n = 64) and from 12 tertiary care hospitals located across India (n = 25) during 2016-18, showing aztreonam/avibactam MICs ≥1 mg/L (≥4 times the aztreonam epidemiological cut-off) were included in this study. The MICs of antibiotics were determined using the reference broth microdilution method. Results Four-amino-acid inserts [YRIK (n = 30) and YRIN (n = 53)] were found in 83/89 isolates. Among 83 isolates, 65 carried carbapenemase genes [blaNDM (n = 39), blaOXA-48-like (n = 11) and blaNDM + blaOXA-48-like (n = 15)] and 18 isolates produced ESBLs/class C β-lactamases only. At least 16 unique STs were noted. Cefepime/zidebactam demonstrated potent activity, with all isolates inhibited at ≤1 mg/L. Comparator antibiotics including ceftazidime/avibactam and imipenem/relebactam showed limited activities. Conclusions E. coli isolates concurrently harbouring four-amino-acid inserts in PBP3 and NDM are an emerging therapeutic challenge. Assisted by the PBP2-binding action of zidebactam, the cefepime/zidebactam combination overcomes both target modification (PBP3 insert)- and carbapenemase (NDM)-mediated resistance mechanisms in E. coli.
TL;DR: It is shown that carbapenems, and especially imipenem, penetrate the outer membrane of K. pneumoniae and E. cloacae substantially faster than noncarbapenem β-lactams, and a novel cassette assay is developed, which can simultaneously characterize the permeability of five β- lactams in multidrug-resistant clinical isolates.
Abstract: Poor penetration through the outer membrane (OM) of Gram-negative bacteria is a major barrier of antibiotic development. While β-lactam antibiotics are commonly used against Klebsiella pneumoniae and Enterobacter cloacae, there are limited data on OM permeability especially in K. pneumoniae. Here, we developed a novel cassette assay, which can simultaneously quantify the OM permeability to five β-lactams in carbapenem-resistant K. pneumoniae and E. cloacae. Both clinical isolates harbored a blaKPC-2 and several other β-lactamases. The OM permeability of each antibiotic was studied separately (“discrete assay”) and simultaneously (“cassette assay”) by determining the degradation of extracellular β-lactam concentrations via multiplex liquid chromatography-tandem mass spectrometry analyses. Our K. pneumoniae isolate was polymyxin resistant, whereas the E. cloacae was polymyxin susceptible. Imipenem penetrated the OM at least 7-fold faster than meropenem for both isolates. Imipenem penetrated E. cloacae at least 258-fold faster and K. pneumoniae 150-fold faster compared to aztreonam, cefepime, and ceftazidime. For our β-lactams, OM permeability was substantially higher in the E. cloacae compared to the K. pneumoniae isolate (except for aztreonam). This correlated with a higher OmpC porin production in E. cloacae, as determined by proteomics. The cassette and discrete assays showed comparable results, suggesting limited or no competition during influx through OM porins. This cassette assay allowed us, for the first time, to efficiently quantify the OM permeability of multiple β-lactams in carbapenem-resistant K. pneumoniae and E. cloacae. Characterizing the OM permeability presents a critical contribution to combating the antimicrobial resistance crisis and enables us to rationally optimize the use of β-lactam antibiotics. IMPORTANCE Antimicrobial resistance is causing a global human health crisis and is affecting all antibiotic classes. While β-lactams have been commonly used against susceptible isolates of Klebsiella pneumoniae and Enterobacter cloacae, carbapenem-resistant isolates are spreading worldwide and pose substantial clinical challenges. Rapid penetration of β-lactams leads to high drug concentrations at their periplasmic target sites, allowing β-lactams to more completely inactivate their target receptors. Despite this, there are limited tangible data on the permeability of β-lactams through the outer membranes of many Gram-negative pathogens. This study presents a novel, cassette assay, which can simultaneously characterize the permeability of five β-lactams in multidrug-resistant clinical isolates. We show that carbapenems, and especially imipenem, penetrate the outer membrane of K. pneumoniae and E. cloacae substantially faster than noncarbapenem β-lactams. The ability to efficiently characterize the outer membrane permeability is critical to optimize the use of β-lactams and combat carbapenem-resistant isolates.
TL;DR: The spread of ADC-30 co-producing KPC-2 along with other β-lactamases among carbapenem resistant A. baumannii strains obtained from ICU patients in two Indian hospitals is reported.
TL;DR: It is proposed that AST-120 reduces indole level, consequently suppresses indole effects on induction of drug tolerance and virulence in Escherichia coli including enterohaemorrhagic strains, and suggests another benefit of AST- 120, i.e., that it assists antibacterial chemotherapy.
Abstract: AST-120 (Kremezin) is used to treat progressive chronic kidney disease (CKD) by adsorbing uremic toxin precursors produced by gut microbiota, such as indole and phenols. In this study, we propose that AST-120 reduces indole level, consequently suppresses indole effects on induction of drug tolerance and virulence in Escherichia coli including enterohaemorrhagic strains. In experiments, AST-120 adsorbed both indole and tryptophan, a precursor of indole production, and led to decreased expression of acrD and mdtEF which encode drug efflux pumps, and elevated glpT, which encodes a transporter for fosfomycin uptake and increases susceptibility to aztreonam, rhodamine 6G, and fosfomycin. AST-120 also decreased the production of EspB, which contributes to pathogenicity of enterohaemorrhagic E. coli (EHEC). Aztreonam, ciprofloxacin, minocycline, trimethoprim, and sulfamethoxazole were also adsorbed by AST-120. However, fosfomycin, in addition to rifampicin, colistin and amikacin were not adsorbed, thus AST-120 can be used together with these drugs for therapy to treat infections. These results suggest another benefit of AST-120, i.e., that it assists antibacterial chemotherapy.
TL;DR: It is proved that AMPs can synergize with BLIs and that this phenomenon can be exploited to sensitize bacteria to antibiotics.
TL;DR: Single-dose aztreonam is not a reliable treatment for gonorrhea at the pharynx but may be useful for men with gonococcal urethritis and beta-lactam allergy.
Abstract: The threat of ceftriaxone-resistant Neisseria gonorrhoeae necessitates new gonorrhea treatment regimens. Repurposing older antibiotics not routinely used for N. gonorrhoeae may expeditiously identify new therapies. Ideally, all recommended therapies should eradicate gonorrhea at the pharynx. Between April and September 2019, we enrolled men in an open-label, one-arm clinical trial of single-dose intramuscular aztreonam (2 g). Enrollment criterion included (i) nucleic acid amplification test (NAAT)-positive pharyngeal gonorrhea for ≤14 days or (ii) Gram stain-positive gonococcal urethritis plus report of performing oral sex in ≤2 months. At enrollment, we collected cultures from NAAT-positive or screening sites, and men returned 3 to 8 days following treatment for a test of cure (TOC) by culture. The per-protocol analysis required men to be culture positive at enrollment and to return for TOC. We calculated efficacy as the number of subjects with negative culture at TOC divided by the number culture positive at enrollment by anatomic site. Thirty-two men enrolled in the study; 21 were pharyngeal NAAT positive, and 11 had gonococcal urethritis. The per-protocol analysis included 17 men, 6 with pharyngeal, 9 with urethral, and 4 with rectal gonococcal infections. Aztreonam cured 2 of 6 pharyngeal infections (33%; 95% confidence interval [CI], 4.3% to 78%) and 3 of 4 rectal infections (75%; 95% CI, 19% to 99%). All 11 men with urethritis were cured (100%; 95% CI, 66% to 100%). The aztreonam MIC90 was 0.5 μg/ml (range, 0.06 to 2.0 μg/ml). All treatment failures occurred at a MIC of ≥0.25 μg/ml. Single-dose aztreonam is not a reliable treatment for gonorrhea at the pharynx but may be useful for men with gonococcal urethritis and beta-lactam allergy. (This study has been registered at ClinicalTrials.gov under identifier NCT03867734.)
TL;DR: Ceftazidime/avibactam can be an appropriate treatment for patients with infections caused by Enterobacterales or P. aeruginosa and for whom treatment options may be limited, according to CLSI guidelines.
Abstract: OBJECTIVES We report the in vitro activity of ceftazidime/avibactam and comparators against 7729 Enterobacterales isolates and 2053 Pseudomonas aeruginosa isolates collected from six Latin American countries between 2015 and 2017. METHODS A central reference laboratory performed antimicrobial susceptibility testing using broth microdilution panels according to CLSI guidelines. The presence of β-lactamases was confirmed using multiplex PCR assays. RESULTS Susceptibility rates among Enterobacterales were highest for ceftazidime/avibactam (99.3%, MIC90 = 0.5 mg/L), meropenem (95.4%, MIC90 = 0.12 mg/L) and amikacin (93.5%, MIC90 = 8 mg/L). High susceptibility rates were observed for ceftazidime/avibactam in all six countries. The majority of carbapenemase-positive isolates among Enterobacterales (N = 366, 4.7%) were susceptible to ceftazidime/avibactam (86.9%), colistin (76.8%) and amikacin (60.9%); MBL-positive isolates (N = 49, 0.6%) were susceptible only to colistin (79.6%), with a minority susceptible to amikacin (49.0%), aztreonam and levofloxacin (both 30.6%). Highest rates of susceptibility among P. aeruginosa isolates were for colistin (99.2%) and ceftazidime/avibactam (86.6%), with rates of susceptibility to all other agents being <80.0%. MDR P. aeruginosa isolates (N = 712, 34.7%) had a high rate of susceptibility to colistin (98.9%); the rate of susceptibility to ceftazidime/avibactam was 61.4% and <50.0% to all other comparator agents. A total of 235 (11.4%) isolates of P. aeruginosa were carbapenemase positive and 148 (7.2%) were MBL positive; both subsets had high rates of susceptibility to colistin (98.3% and 100%, respectively). CONCLUSIONS Ceftazidime/avibactam susceptibility rates in Latin American countries are stable and high; ceftazidime/avibactam can be an appropriate treatment for patients with infections caused by Enterobacterales or P. aeruginosa and for whom treatment options may be limited.