Β-lactamase Inhibitor Combinations Research Articles

Antimicrobial susceptibility of enterobacterales causing bloodstream infection in United States medical centres: comparison of aztreonam-avibactam with beta-lactams active against carbapenem-resistant enterobacterales

BackgroundBloodstream infection (BSI) is associated with poor outcomes especially when effective antimicrobial therapy and control of infection source are delayed. As the frequency of Enterobacterales producing metallo-β-lactamases (MBL) and/or OXA-48–like carbapenemases is increasing in some United States (US) medical centres, effective antimicrobials to treat the infections caused by these organisms are urgently needed. Aztreonam-avibactam is under clinical development for treatment of infections caused by Gram-negative bacteria, including MBL producers.ObjectivesTo evaluate the antimicrobial susceptibility of Enterobacterales causing BSI in US medical centres and compare the activity of aztreonam-avibactam with ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, cefiderocol, and other antimicrobials used to treat BSI.Methods4,802 Enterobacterales were consecutively collected (1/patient) from 72 US medical centres in 2020–2022 and susceptibility tested by broth microdilution. Aztreonam-avibactam was tested with avibactam at a fixed concentration of 4 mg/L. A pharmacokinetic/pharmacodynamic susceptible breakpoint of ≤ 8 mg/L was applied for aztreonam-avibactam for comparison. Carbapenem-resistant Enterobacterales (CRE) isolates were tested for β-lactamase–encoding genes using Next-generation sequencing.ResultsAztreonam-avibactam was highly active against Enterobacterales; only 2 isolates showed aztreonam-avibactam MICs > 8 mg/L: 1 meropenem-susceptible E. coli and 1 K. aerogenes (CRE). All carbapenemase producers and 98.0% of CRE were inhibited at an aztreonam-avibactam MIC of ≤ 8 mg/L. CRE susceptibility rates were 81.6% for ceftazidime-avibactam, 65.3% for meropenem-vaborbactam, 61.2% for imipenem-relebactam, and 87.8% for cefiderocol. Aztreonam-avibactam retained activity (MIC, ≤ 8 mg/L) against all (100.0%) meropenem-vaborbactam nonsusceptible (n = 17), 99.5% of imipenem-relebactam nonsusceptible (n = 206), and 90.0% of ceftazidime-avibactam nonsusceptible (n = 10) isolates. The most common carbapenemases were KPC-2/3 (57.1% of CREs), OXA-48–like (16.3%), and NDM (14.3%). A carbapenemase gene was not observed in 12.3% of CREs. Ceftazidime-avibactam and meropenem-vaborbactam were active against 100.0% of KPC producers, but ceftazidime-avibactam showed limited activity against MBL producers and meropenem-vaborbactam showed limited activity against OXA-48–like and MBL producers. The most active non–β-lactam comparators against CRE were gentamicin (49.0% susceptible) and amikacin (44.9% susceptible).ConclusionsAztreonam-avibactam demonstrated potent activity against a large collection of Enterobacterales isolated from patients with BSI in US hospitals, including CRE, MBL producers, and isolates resistant to recently approved β-lactamase inhibitor combinations.

Analysis of the changes of bacterial spectrum and drug resistance in sputum culture of ICU children in a hospital of pediatric in Jiangsu Province from 2017 to 2022

Objective: To investigate the changes of the distribution and drug resistance profile of bacteria from ICU children with lower respiratory tract infection (LRTI) in Suzhou City, Jiangsu Province from 2017 to 2022. Methods: From January 2017 to December 2022, a cross-sectional observational study on the bacterial spectrum analysis among intensive care unit (ICU) children with LRTI was conducted in Children's Hospital of Soochow University. The bacteria was cultivated by culture methods from sputum samples, and identified by MALDI-TOF mass spectrometry. Drug sensitivity tests were performed by the VITEK2 Compact fully automated analysis system and the paper slide method. The χ2 test or Fisher's exact probability was used to analyze the changes of the distribution of sputum culture-positive bacteria and drug resistance in ICU children. Results: The overall detection rate of sputum culture was 42.06% (1 182/2 810). Staphylococcus aureus (25.63%,303/1 182), Acinetobacter baumannii (13.62%,161/1 182) and Haemaphilus influenzae (13.28%,157/1 182) were the top three. Proportions of Acinetobacter baumannii (17.90% vs. 11.02%,χ²=11.17, P=0.001), especially carbapenem-resistant Acinetobacter baumannii (43.70% vs. 23.50%, χ²=15.21, P<0.001) increased significantly from 2020 to 2022. However, the proportions of Haemophilus influenzae (8.50% vs. 16.19%, χ²=14.27, P<0.001), Streptococcus pneumoniae (8.50% vs. 15.92%, χ²=13.42, P<0.001) and extended-spectrum-lactamase producing Escherichia coli (8.89% vs. 18.00%, χ²=5.45, P=0.025) decreased. Drug resistant results showed that Acinetobacter baumannii was obviously more resistant to imipenem (χ²=4.43, P=0.035) and levofloxacin (χ²=12.53, P<0.001), while more sensitive to minocycline (χ²=8.34, P=0.004). Escherichia coli showed a significant increase in resistance to piperacillin tazobactam (χ²=8.29, P=0.008) and cefoperazone sulbactam (χ²=5.07, P=0.024) from 2020 to 2022; Klebsiella pneumoniae consistently maintained a resistance rate of more than 60% to first and second-generation cephalosporins, and remain susceptible to quinolones and carbapenems. Staphylococcus aureus remained highly susceptible to levofloxacin (drug resistance rate: 2.31%,7/303) and sulfamethoxazole/trimethoprim (drug resistance rate: 4.95%,15/303) from 2020 to 2022. Conclusion: Higher detection and resistance rates of Acinetobacter baumannii from sputum culture in ICU children from 2020 to 2022 were explored. Resistance of Escherichia coli to β-lactamase inhibitor combinations was more serious. Regular monitoring the changes of the etiology of respiratory tract infections in ICU Children is particularly important for the prevention and treatment of multidrug-resistant bacterial infections.

Evaluation of gradient strip diffusion for susceptibility testing of aztreonam-avibactam in metallo-β-lactamase-producing Enterobacterales.

The emergence of metallo-β-lactamase (MBL)-producing Enterobacterales presents unique clinical treatment challenges. Recently developed β-lactam/ β-lactamase inhibitor combination agents, while effective against other carbapenemase-producing organisms, are notably ineffective against MBL producers. While MBLs do not hydrolyze monobactams (aztreonam), many MBL-producing organisms are resistant to aztreonam through alternate mechanisms, leaving cefiderocol as the sole monotherapy treatment option recommended for MBL producers. Recent guidelines for the treatment of MBL-harboring organisms have added combination therapy with aztreonam and ceftazidime-avibactam, using ceftazidime-avibactam as a source of the β-lactamase inhibitor avibactam. Current laboratory testing options for the combination of aztreonam-avibactam are limited to broth microdilution (BMD) and broth disk elution (BDE) methods, which are not practical in most clinical laboratories. In this study, we evaluated the performance of aztreonam/avibactam gradient strips on 103 MBL-producing Enterobacterales patient isolates as well as an additional 31 isolates from the CDC AR Bank. All MBL Enterobacterales patient isolates included in this study harbored a New Delhi metallo-β-lactamase (blaNDM) gene. Essential agreement of gradient strip minimal inhibitory concentrations (MICs) for patient isolates compared to BMD was 93.2%. While there are no established breakpoints for aztreonam-avibactam, category agreement (CA) for patient isolates was 97.1% when using the CLSI aztreonam breakpoints. There were no major or very major errors observed. There were three minor errors. Precision for aztreonam-avibactam gradient strip diffusion was 100%. These data demonstrate that the use of gradient strip diffusion for aztreonam-avibactam MIC determination in MBL-producing Enterobacterales is a viable option for clinical laboratories.

Survival of infection with TEM β-lactamase-producing Escherichia coli with Pan-β-lactam resistance

Antimicrobial resistance is a critical global health issue, significantly contributing to patient mortality. Recent antibiotic developments have aimed to counteract carbapenemase-producing Enterobacterales; however, the impact of their use on the emergence of antibiotic resistance is unknown. This study investigates the first case of a non-carbapenemase-producing, pan-β-lactam-resistant Escherichia coli strain from a patient previously treated with ceftolozane-tazobactam and cefiderocol. This study describes the clinical progression of a 39-year-old ICU patient who developed multiple infections, culminating in the isolation of a pan-β-lactam-resistant E. coli strain (EC554). The resistance profile was characterised through MIC determination, whole-genome sequencing, the use of the β-lactam inactivation method, RT-qPCR, efflux pump inhibition assays, outer membrane protein analysis, and blaTEM transformation. The EC554 isolate displayed resistance to all tested β-lactams and β-lactam-β-lactamase inhibitor combinations. Whole-genome sequencing revealed four plasmids in EC554, with the only β-lactamase gene being blaTEM-252 on the pEC554-PBR-X1-X1 plasmid. We found that the extremely resistant phenotype was attributable to a combination of different mechanisms: a high expression of TEM-252, efflux pump activity, porin loss, and PBP3 mutations. The findings illustrate the complex interplay of multiple resistance mechanisms in E. coli, highlighting the potential for high-level resistance even without carbapenemase production. This study underscores the importance of comprehensively characterising resistance mechanisms in order to inform effective treatment strategies and mitigate the spread of resistant strains.

An investigation of broad-spectrum antibiotic-induced liver injury based on the FDA Adverse Event Reporting System and retrospective observational study

Tazobactam/piperacillin and meropenem are commonly used as an empiric treatment in patients with severe bacterial infections. However, few studies have investigated the cause of tazobactam/piperacillin- or meropenem-induced liver injury in them. Our objective was to evaluate the association between tazobactam/piperacillin or meropenem and liver injury in the intensive care unit patients. We evaluated the expression profiles of antibiotics-induced liver injury using the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. Further, in the retrospective observational study, data of patients who initiated tazobactam/piperacillin or meropenem in the intensive care unit were extracted. In FAERS database, male, age, the fourth-generation cephalosporin, carbapenem, β-lactam and β-lactamase inhibitor combination, and complication of sepsis were associated with liver injury (p < 0.001). In the retrospective observational study, multivariate logistic regression analyses indicated that the risk factors for liver injury included male (p = 0.046), administration period ≥ 7 days (p < 0.001), and alanine aminotransferase (p = 0.031). Not only administration period but also sex and alanine aminotransferase should be considered when clinicians conduct the monitoring of liver function in the patients receiving tazobactam/piperacillin or meropenem.

Assessment of in vitro activity of ceftazidime/avibactam on carbapenemase-producing Enterobacterales from Iran: An experimental study.

The prevalence of carbapenemase-producing Enterobacterales (CPE) continues to increase worldwide. Combination of β-lactam and novel β-lactamase inhibitors introduce a revolutionary treatment option for CPE. Ceftazidime/avibactam (CAZ/AVB) has been recently developed for treatment of severe infections caused by multidrug-resistant bacteria. We aimed to evaluate in vitro activity of CAZ/AVB on a collection of 85 ESBL-producing-carbapenemase negative and CPE from Iran. ESBL and carbapenemase production was phenotypically confirmed by combined disk test and modified carbapenem inactivation method respectively. The presence of clinically important carbapenemase encoding genes was examined using PCR. Susceptibility of all isolates to CAZ/AVB was determined using discs containing 30 μg ceftazidime +20 μg avibactam (AVB). Minimum inhibitory concentrations (MICs) of CAZ/AVB in 28 CPE (4 Escherichia coli and 24 Klebsiella pneumoniae) was determined by gradient diffusion method using MIC test strips (0.016-256 mg/L ceftazidime +4 mg/L AVB). All phenotypically identified ESBL positive-carbapenemase negative isolates were found to be susceptible to CAZ/AVB. Among the carbapenem resistant isolates, CAZ/AVB showed potent inhibitory activity against all OXA-48-like (MIC ranges 0.125/4-0.75/4 mg/L) and KPC positive isolates (MIC ranges <0.016/4-0.19/4 mg/L). However, AVB could not restore the activity of ceftazdime against isolates producing metallo-β-lactamases (MLBs) including VIM, NDM (MIC > 256/4 mg/L) and IMP (MIC > 8/4 mg/L). Our data highlighted the excellent in vitro performance of CAZ/AVB against ESBL-producing and CPE suggesting that this combination can efficiently be used as therapeutic option for management of CPE infections particularly in regions with high prevalence of KPC and/or OXA-48-like positive but MBL-negative Enterobacterales.

Activity of Aztreonam/Avibactam and Recently Approved β-Lactamase Inhibitor Combinations against Enterobacterales and Pseudomonas aeruginosa from Intensive Care Unit and Non-Intensive Care Unit Patients.

We evaluated the activities of aztreonam/avibactam and recently approved β-lactamase inhibitor combinations (BLICs) to compare the antimicrobial susceptibility patterns of Enterobacterales and Pseudomonas aeruginosa isolated from intensive care unit (ICU) and non-ICU patients. Clinical isolates (1/patient) were consecutively collected from 72 United States medical centres in 2020-2022 and susceptibility tested by broth microdilution. The results for 5421 isolates from ICU patients were analysed and compared to those for 20,649 isolates from non-ICU patients. Isolates from ventilator-associated pneumonia patients were analysed separately. Aztreonam/avibactam inhibited 100.0%/>99.9% Enterobacterales and 100.0%/98.3% of carbapenem-resistant Enterobacterales (CRE) from ICU/non-ICU patients at ≤8 mg/L, respectively. The CRE susceptibility rates were 88.5%/82.9% for ceftazidime/avibactam, 82.1%/81.2% for meropenem/vaborbactam, and 78.2%/72.6% for imipenem/relebactam among ICU/non-ICU isolates. Among the P. aeruginosa isolates from ICU/non-ICU patients, the susceptibility rates were 96.3%/97.6% for ceftazidime/avibactam, 97.2/98.4% for ceftolozane/tazobactam, 97.1%/98.0% for imipenem/relebactam, 77.8%/84.6% for piperacillin/tazobactam, and 76.9%/85.8% for meropenem; aztreonam/avibactam inhibited 78.0%/81.9% of P. aeruginosa at ≤8 mg/L. In summary, lower susceptibility rates were observed among ICU than non-ICU isolates. Aztreonam/avibactam exhibited potent in vitro activity and broad-spectrum activity against Enterobacterales from ICU and non-ICU patients, including CRE and isolates non-susceptible to newer BLICs. Against P. aeruginosa, aztreonam/avibactam showed a spectrum of activity comparable to that of piperacillin/tazobactam, meropenem, and ceftazidime.

Unveiling the ecological landscape of bacterial β-lactam resistance in Delhi-national capital region, India: An emerging health concern

Inappropriate antibiotic use not only amplifies the threat of antimicrobial resistance (AMR), moreover exacerbates the spread of resistant bacterial strains and genes in the environment, underscoring the critical need for effective research and interventions. Our aim is to assess the prevalence and resistance characteristics of β-lactam resistant bacteria (BLRB) and β-lactamase resistant bacterial genes (BLRBGs) under various environmental conditions within Delhi NCR, India. Using a culture-dependent method, we isolated 130 BLRB from 75 different environmental samples, including lakes, ponds, the Yamuna River, agricultural soil, aquatic weeds, drains, dumping yards, STPs, and gaushalas. Tests for antibiotic susceptibility were conducted in addition to phenotypic and genotypic identification of BLs and integron genes. The water and sediment samples recorded an average bacterial abundance of 3.6 × 106 CFU/mL and an average ampicillin-resistant bacterial count of 2.2 × 106 CFU/mL, which can be considered a potent reservoir of BLRB and BLRBGs. The majority of the BLRB discovered are opportunistic pathogens from the Bacillus, Aeromonas, Pseudomonas, Enterobacter, Escherichia, and Klebsiella genera, with Multiple Antibiotic Resistance (MAR) index ≥0.2 against a wide variety of β-lactams and β-lactamase (BLs) inhibitor combinations. The antibiotic resistance pattern was similar in the case of bacteria isolated from STPs. Meanwhile, bacteria isolated from other sources were diverse in their antibiotic resistance profile. Interestingly, we discovered that 10 isolates of various origins produce both Extended Spectrum BLs and Metallo BLs, as well as found harboring blaTEM, blaCTX, blaOXA, blaSHV, int-1, and int-3 genes. Enterobacter cloacae (S50/A), a common nosocomial pathogen isolated from Yamuna River sediment samples at Nizamuddin point, possesses three BLRBGs (blaTEM, blaCTX, and blaOXA) and a MAR index of 1.0, which is a major cause for concern. Therefore, identifying the source, origin and dissemination of BLRB and BLRGs in the environment is of the utmost importance for designing effective mitigation approaches to reduce a load of antimicrobial resistance factors in the environmental settings.

Genomic and Functional Characterization of CTX-M-15-Producing Klebsiella pneumoniae ST307 Isolated from Imported Leopard Tortoises in Germany

The Klebsiella pneumoniae ST307 clone, identified in the mid-1990s, has emerged as a global antimicrobial-resistant (AMR) high-risk clone, significantly contributing to the global health challenge also posed by other AMR K. pneumoniae lineages. The acquisition of a blaCTX-M-15-carrying plasmid has facilitated its widespread dissemination. At Europe’s major transport hub for the movement of live animals, Frankfurt Airport, a shipment of 20 live leopard tortoises was sampled during German border control in 2014. Phylogenetic analysis (MLST) identified a K. pneumoniae ST307 strain, prompting further investigation. Our analysis revealed the presence of a ~193 kb plasmid carrying a broad range of AMR genes, including blaCTX-M-15, blaTEM-1B, blaOXA-1, aac(3)-IIa, aac(6′)-Ib-cr, aph(3″)-Ib, aph(6)-Id, and qnrB1. Additionally, mutations in the quinolone resistance-determining region in gyrA (S83I) and parC (S80I) were detected. Phenotypic testing demonstrated resistance of the isolate to the most common antimicrobials used in both human and veterinary medicine; exceptions included carbapenems and newer β-lactamase inhibitor combinations. Because the role of imported exotic animals in the dissemination of AMR genes is largely deficient, the present study fills yet missing mosaic pieces in the complete picture of extended-spectrum β-lactamase (ESBL)-producing Enterobacterales.

Revisiting the Checkerboard to Inform Development of β-Lactam/β-Lactamase Inhibitor Combinations.

A two-dimensional "checkerboard" array employing systematic titration (e.g., serial two-fold dilutions) is a well-established in vitro method for exploring the antibacterial effects of novel drug combinations. Minimum inhibitory concentrations (MICs) on the checkerboard are isoeffective points at which the antibiotic potency is the same. Representations of checkerboard MIC curves for a β-lactam and β-lactamase inhibitor combination are used in hypothetical "thought experiments" and reveal the ways in which current practices can be improved. Because different types of response (i.e., independence vs. additivity vs. one effective agent; interaction vs. noninteraction) produce different MIC curves, data from different strains/isolates should not be pooled indiscriminately, as the composition of a pooled dataset will influence any derived pharmacokinetic/pharmacodynamic (PK/PD) index. Because the β-lactamase inhibitor threshold concentration (CT) parameter is a function of the β-lactam partner dosing regimen, it is not possible to derive a universal PK/PD index target based on CT. Alternative susceptibility testing methods represent different planes through the checkerboard; a fixed ratio method is less prone to bias for all β-lactam and β-lactamase inhibitor combinations. Susceptibility test MICs will often not reflect the sensitivity of the strain/isolate to the β-lactamase inhibitor, so the use of these MICs to normalize PK/PD indices is inappropriate.

Epidemiology and antimicrobial susceptibility profiles of Enterobacterales causing bloodstream infections before and during COVID-19 pandemic: Results of the Study for Monitoring Antimicrobial Resistance Trends (SMART) in Taiwan, 2018–2021

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic has contributed to the spread of antimicrobial resistance, including carbapenem-resistant Enterobacterales. MethodsThis study utilized data from the Study for Monitoring Antimicrobial Resistance Trends (SMART) surveillance program in Taiwan. Enterobacterales from patients with bloodstream infections (BSIs) were collected and subjected to antimicrobial susceptibility testing and β-lactamase gene detection using a multiplex PCR assay. Statistical analysis was conducted to compare susceptibility rates and resistance genes between time periods before (2018–2019) and during the COVID-19 pandemic (2020–2021). ResultsA total of 1231 Enterobacterales isolates were collected, predominantly Escherichia coli (55.6%) and Klebsiella pneumoniae (29.2%). The proportion of nosocomial BSIs increased during the COVID-19 pandemic (55.5% vs. 61.7%, p < 0.05). Overall, susceptibility rates for most antimicrobial agents decreased, with Enterobacterales from nosocomial BSIs showing significantly lower susceptibility rates than those from community-acquired BSIs. Among 123 Enterobacterales isolates that underwent molecular resistance mechanism detection, ESBL, AmpC β-lactamase, and carbapenemase genes were detected in 43.1%, 48.8% and 16.3% of the tested isolates, respectively. The prevalence of carbapenemase genes among carbapenem-resistant Enterobacterales increased during the pandemic, although the difference was not statistically significant. Two novel β-lactamase inhibitor combinations, imipenem-relebactam and meropenem-vaborbactam, preserved good efficacy against Enterobacterales. However, imipenem-relebactam showed lower in vitro activity against imipenem-non-susceptible Enterobacterales than that of meropenem-vaborbactam. ConclusionsThe COVID-19 pandemic appears to be associated with a general decrease in antimicrobial susceptibility rates among Enterobacterales causing BSIs in Taiwan. Continuous surveillance is crucial to monitor antimicrobial resistance during the pandemic and in the future.

Structure Guided Discovery of Novel Pan Metallo-β-Lactamase Inhibitors with Improved Gram-Negative Bacterial Cell Penetration.

The use of β-lactam (BL) and β-lactamase inhibitor combination to overcome BL antibiotic resistance has been validated through clinically approved drug products. However, unmet medical needs still exist for the treatment of infections caused by Gram-negative (GN) bacteria expressing metallo-β-lactamases. Previously, we reported our effort to discover pan inhibitors of three main families in this class: IMP, VIM, and NDM. Herein, we describe our work to improve the GN coverage spectrum in combination with imipenem and relebactam. This was achieved through structure- and property-based optimization to tackle the GN cell penetration and efflux challenges. A significant discovery was made that inhibition of both VIM alleles, VIM-1 and VIM-2, is essential for broad GN coverage, especially against VIM-producing P. aeruginosa. In addition, pharmacokinetics and nonclinical safety profiles were investigated for select compounds. Key findings from this drug discovery campaign laid the foundation for further lead optimization toward identification of preclinical candidates.

Cefepime–Taniborbactam in Complicated Urinary Tract Infection

BackgroundCarbapenem-resistant Enterobacterales species and multidrug-resistant Pseudomonas aeruginosa are global health threats. Cefepime–taniborbactam is an investigational β-lactam and β-lactamase inhibitor combination with activity against Enterobacterales species and P. aeruginosa expressing serine and metallo-β-lactamases.MethodsIn this phase 3, double-blind, randomized trial, we assigned hospitalized adults with complicated urinary tract infection (UTI), including acute pyelonephritis, in a 2:1 ratio to receive intravenous cefepime–taniborbactam (2.5 g) or meropenem (1 g) every 8 hours for 7 days; this duration could be extended up to 14 days in case of bacteremia. The primary outcome was both microbiologic and clinical success (composite success) on trial days 19 to 23 in the microbiologic intention-to-treat (microITT) population (patients who had a qualifying gram-negative pathogen against which both study drugs were active). A prespecified superiority analysis of the primary outcome was performed after confirmation of noninferiority.ResultsOf the 661 patients who underwent randomization, 436 (66.0%) were included in the microITT population. The mean age of the patients was 56.2 years, and 38.1% were 65 years of age or older. In the microITT population, 57.8% of the patients had complicated UTI, 42.2% had acute pyelonephritis, and 13.1% had bacteremia. Composite success occurred in 207 of 293 patients (70.6%) in the cefepime–taniborbactam group and in 83 of 143 patients (58.0%) in the meropenem group. Cefepime–taniborbactam was superior to meropenem regarding the primary outcome (treatment difference, 12.6 percentage points; 95% confidence interval, 3.1 to 22.2; P=0.009). Differences in treatment response were sustained at late follow-up (trial days 28 to 35), when cefepime–taniborbactam had higher composite success and clinical success. Adverse events occurred in 35.5% and 29.0% of patients in the cefepime–taniborbactam group and the meropenem group, respectively, with headache, diarrhea, constipation, hypertension, and nausea the most frequently reported; the frequency of serious adverse events was similar in the two groups.ConclusionsCefepime–taniborbactam was superior to meropenem for the treatment of complicated UTI that included acute pyelonephritis, with a safety profile similar to that of meropenem. (Funded by Venatorx Pharmaceuticals and others; CERTAIN-1 ClinicalTrials.gov number, NCT03840148.)

Activity of aztreonam-avibactam against Enterobacterales resistant to recently approved beta-lactamase inhibitor combinations collected in Europe, Latin America, and the Asia-Pacific Region (2020–2022)

BackgroundAztreonam-avibactam is under clinical development for treatment of infections caused by carbapenem-resistant Enterobacterales (CRE), especially those resistant to recently approved β-lactamase inhibitor combinations (BLICs). ObjectivesTo evaluate a large collection of CRE isolates, including those non-susceptible to ceftazidime-avibactam, meropenem-vaborbactam, and/or imipenem-relebactam. MethodsOverall, 24 580 Enterobacterales isolates were consecutively collected (1/patient) in 2020–2022 from 64 medical centres located in Western Europe (W-EU), Eastern Europe (E-EU), Latin America (LATAM), and the Asia-Pacific region (APAC). Of those, 1016 (4.1%) were CRE. Isolates were susceptibility tested by broth microdilution. CRE isolates were screened for carbapenemase genes by whole genome sequencing. ResultsAztreonam-avibactam inhibited 99.6% of CREs at ≤8 mg/L. Ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-relebactam were active against 64.6%, 57.4%, and 50.7% of CRE isolates, respectively; most of the non-susceptible isolates carried metallo-beta-lactamases. Aztreonam-avibactam was active against ≥98.9% of isolates non-susceptible to these BLICs. The activity of these BLICs varied by region, with highest susceptibility rates observed in W-EU (76.9% for ceftazidime-avibactam, 72.5% for meropenem-vaborbactam, 63.8% for imipenem-relebactam) and the lowest susceptibility rates identified in the APAC region (39.9% for ceftazidime-avibactam, 37.8% for meropenem-vaborbactam, and 27.5% for imipenem-relebactam). The most common carbapenemase types overall were KPC (44.6% of CREs), NDM (29.9%), and OXA-48–like (16.0%). KPC predominated in LATAM (64.1% of CREs in the region) and W-EU (61.1%). MBL occurrence was highest in APAC (59.5% of CREs in the region), followed by LATAM (34.0%), E-EU (28.9%), and W-EU (23.6%). ConclusionsAztreonam-avibactam demonstrated potent activity against CRE isolates resistant to ceftazidime-avibactam, meropenem-vaborbactam, and/or imipenem-relebactam independent of the carbapenemase produced.

In vitro activity of sulbactam-durlobactam against colistin-resistant and/or cefiderocol-non-susceptible, carbapenem-resistant Acinetobacter baumannii collected in U.S. hospitals.

The activity of a novel β-lactamase inhibitor combination, sulbactam-durlobactam (SUL-DUR), was tested against 87 colistin-resistant and/or cefiderocol-non-susceptible carbapenem-resistant Acinetobacter baumannii clinical isolates collected from U.S. hospitals between 2017 and 2019. Among them, 89% and 97% were susceptible to SUL-DUR and imipenem plus SUL-DUR, with MIC50/MIC90 values of 2 µg/mL/8 µg/mL and 1 µg/mL/4 µg/mL, respectively. The presence of amino acid substitutions in penicillin-binding protein 3, including previously reported A515V or T526S, was associated with SUL-DUR non-susceptibility.

Clarithromycin for early anti-inflammatory responses in community-acquired pneumonia in Greece (ACCESS): a randomised, double-blind, placebo-controlled trial

Addition of macrolide antibiotics to β-lactam antibiotics for the treatment of patients in hospital with community-acquired pneumonia is based on results from observational studies and meta-analyses rather than randomised clinical trials. We investigated if addition of the macrolide clarithromycin to treatment with a β-lactam antibiotic in this population could improve early clinical response-the new regulatory endpoint for community-acquired pneumonia-and explored the possible contribution of modulation of the inflammatory host response to that outcome. The ACCESS trial was a phase 3 prospective, double-blind, randomised controlled trial, in which adults in hospital with community-acquired pneumonia who had systemic inflammatory response syndrome, Sequential Organ Failure Assessment (SOFA) score of 2 or more, and procalcitonin 0·25 ng/mL or more were enrolled in 18 internal medicine departments of public Greek hospitals. Patients were randomly assigned (1:1) by computer-generated block randomisation to standard of care medication (including intravenous administration of a third-generation cephalosporin or intravenous administration of β-lactam plus β-lactamase inhibitor combination) plus either oral placebo or oral clarithromycin 500 mg twice daily for 7 days. Investigators, staff, and patients were masked to group allocation. The primary composite endpoint required that patients fulfilled both of the following conditions after 72 hours (ie, day 4 of treatment): (1) decrease in respiratory symptom severity score of 50% or more as an indicator of early clinical response and (2) decrease in SOFA score of at least 30% or favourable procalcitonin kinetics (defined as ≥80% decrease from baseline or procalcitonin <0·25 ng/mL), or both, as an indicator of early inflammatory response. Participants who were randomly assigned and received allocated treatment were included in the primary analysis population. This trial is complete and is registered with the EU Clinical Trials Register (2020-004452-15) and ClinicalTrials.gov (NCT04724044). Patients were enrolled between Jan 25, 2021, and April 11, 2023, and 278 individuals were randomly allocated to receive standard of care in combination with either clarithromycin (n=139) or placebo (n=139). 134 patients in the clarithromycin group (five withdrew consent) and 133 patients in the placebo group (six withdrew consent) were included in the analysis of the primary endpoint. The primary endpoint was met in 91 (68%) patients in the clarithromycin group and 51 (38%) patients in the placebo group (difference 29·6% [95% CI 17·7-40·3]; odds ratio [OR] 3·40 [95% CI 2·06-5·63]; p<0·0001). Serious treatment-emergent adverse events (TEAEs) occurred in 58 (43%) patients in the clarithromycin group and 70 (53%) patients in the placebo group (difference 9·4% [95% CI -2·6 to 20·9]; OR 0·67 [95% CI 0·42 to 1·11]; p=0·14). None of the serious TEAEs was judged to be related to treatment assignment. Addition of clarithromycin to standard of care enhances early clinical response and attenuates the inflammatory burden of community-acquired pneumonia. The mechanism of benefit is associated with changes in the immune response. These findings suggest the importance of adding clarithromycin to β-lactams for treatment of patients in hospital with community-acquired pneumonia to achieve early clinical response and early decrease of the inflammatory burden. Hellenic Institute for the Study of Sepsis and Abbott Products Operations.

Efficacy and safety of novel carbapenem-β-lactamase inhibitor combinations: imipenem-cilastatin/relebactam results from randomized controlled trials.

Gram-negative bacteria is a global public health problem. Treatment options include novel beta-lactamase inhibitors. The objective of this study was to collect information on the efficacy and safety of novel β-lactamase inhibitor combinations such as imipenem-cilastatin/relebactam (IMI/REL). In order to comprehensively evaluate the clinical, microbiological, and adverse events outcomes, a meta-analysis was conducted on clinical trials comparing novel β-lactamase inhibitor combinations with existing comparator therapies. Four studies comprising 948 patients were included in the analysis. IMI/REL therapy demonstrated similar clinical responses to comparators across various treatment visits, including discontinuation of intravenously administered therapy visits [DCIV, RR = 1.00 (0.88, 1.12)], early follow-up visits [EFU, RR = 1.00 (0.89, 1.14)], late follow-up visits [LFU, RR = 1.00 (0.88, 1.13)]. Moreover, no significant difference in the microbiologic response of MITT patients was observed between IMI/REL and comparators across DCIV [RR = 0.99 (0.89, 1.11)], EFU [RR = 1.01 (0.95, 1.07)], and LFU visits [RR = 1.00 (90.94, 1.07)]. In terms of safety, therapy with IMI/REL and comparators exhibited similar risks of at least one adverse event (AE), drug-related AEs, and discontinuation due to AEs. The incidence of serious AEs (SAEs) was significantly lower in the IMI/REL group compared to the comparison groups. The predominant AEs were gastrointestinal disorders, with no significant difference observed between the IMI/REL group and comparators. The clinical and microbiologic response to IMI/REL in the treatment of bacterial infection was comparable to that of the comparator. Furthermore, the incidence of AEs and the tolerability of IMI/REL were similar among the comparators. Based on these findings, IMI/REL can be considered as a viable alternative treatment option.

2598. Activity of Aztreonam-Avibactam and Other β-Lactamase Inhibitor Combinations against Gram-negative Bacteria Isolated from Patients Hospitalized with Pneumonia in US Medical Centers (2020–2022)

Abstract Background Resistance to recently approved β-lactamase inhibitor combinations, such as ceftazidime-avibactam (CAZ-AVI) and meropenem-vaborbactam (MEM-VAB), appears to be increasing among carbapenem-resistant Enterobacterales (CRE) in some US hospitals. We evaluated the frequency and antimicrobial susceptibility of Gram-negative bacteria (GNB) causing pneumonia in US hospitals. Methods Bacterial isolates were consecutively collected (1/patient) from patients hospitalized with pneumonia and the susceptibility of GNBs (3,911 Enterobacterales [ENT] and 2,753 non-fermenters) was evaluated by broth microdilution. Isolates were collected in 69 medical centers in 2020–2022. Susceptibility testing was performed by CLSI broth microdilution in a monitoring laboratory. Aztreonam-avibactam (ATM-AVI) was tested with AVI at fixed 4 mg/L and a pharmacokinetic/pharmacodynamic susceptible (S) breakpoint of ≤ 8 mg/L was applied for comparison. CRE isolates were screened for carbapenemases (CPE) by whole genome sequencing. Results GNB represented 71.1% of organisms. The most common GNB species were P. aeruginosa (22.4% of organisms), K. pneumoniae (8.6%), E. coli (6.6%), S. marcescens (6.2%), S. maltophilia (4.9%), and E. cloacae complex (4.8%). ATM-AVI inhibited 100.0% of ENT at ≤ 8 mg/L and 99.9% at ≤ 4 mg/L and showed potent activity against CRE (MIC50/90, 0.25/1 mg/L; Table). CAZ-AVI and MEM-VAB were active against 89.4% and 88.5% of CREs, respectively. ATM-AVI retained activity against ENT non-S to CAZ-AVI and/or MEM-VAB (n=19; MIC50/90, 0.25/4 mg/L). The most common CPEs were KPC (69.2% of CREs), NDM (9.6%), and SME (4.8%). A CPE gene was not observed in 16.3% of CREs. CAZ-AVI and MEM-VAB were highly active against KPC and SME producers but showed limited activity against MBL producers. The most active comparators against CRE were tigecycline (95.2%S), amikacin (73.1%S), and gentamicin (60.6%S). Among P. aeruginosa, 79.1% were inhibited at ≤8 mg/L of ATM-AVI, 77.2% were MEM-S, and 77.2% were piperacillin-tazobactam-S. ATM-AVI was highly active against S. maltophilia, inhibiting 99.5% of isolates at ≤ 8 mg/L. Conclusion ATM-AVI demonstrated potent in vitro activity against the GNB most isolated from patients with pneumonia in US hospitals. Disclosures Helio S. Sader, MD, PhD, FIDSA, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Rodrigo E. Mendes, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Entasis: Grant/Research Support|GSK: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Leonard R. Duncan, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|CorMedix: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support Timothy Doyle, MS, AbbVie: Grant/Research Support Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|bioMerieux: Grant/Research Support|Cipla: Grant/Research Support|CorMedix: Grant/Research Support|Entasis: Grant/Research Support|Melinta: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support

1949. Activity of Aztreonam-Avibactam against Enterobacterales Resistant to Recently Approved Beta-Lactamase Inhibitor Combinations Collected Worldwide (ex-US; 2020–2022)

Abstract Background Aztreonam-avibactam (ATM-AVI) is under clinical development. Aztreonam is a monobactam stable to hydrolysis by metallo-β-lactamases (MBLs). ATM-AVI has shown activity against MBL-producing, carbapenem-resistant Enterobacterales (CRE) that are resistant to recently approved β-lactamase inhibitor combinations (BLIs) such as ceftazidime-avibactam (CAZ-AVI), meropenem-vaborbactam (MEM-VAB), and imipenem-relebactam (IMI-REL). We evaluated a large collection of CRE isolates nonsusceptible (NS) to these BLIs. Methods 24,580 Enterobacterales isolates were consecutively collected (1/patient) in 2020–2022 from 64 medical centers located in Western Europe (W-EU; 27 centers in 10 countries), Eastern Europe (E-EU; 13 centers in 9 countries), Latin America (LATMA; 8 centers in 6 countries), and the Asia-Pacific region (APAC; 16 centers in 8 countries). Among these isolates, 1,016 (4.1%) were CRE. Isolates were susceptibility tested by CLSI broth microdilution. CRE isolates were screened for carbapenemase (CPE) genes by whole genome sequencing. Results ATM-AVI inhibited 99.6% of CREs (MIC50/90, 0.25/0.5 mg/L) and ≥ 98.9% of CRE isolates NS to CAZ-AVI, MEM-VAB, and/or IMI-REL at ≤8 mg/L (Table). The most active comparators against CREs were CAZ-AVI (64.6%S), MEM-VAB (57.4%S), and IMI-REL (50.7%S). The activity of these BLIs varied widely among region, with highest susceptibility rates observed in W-EU (76.9% for CAZ-AVI, 72.5% for MEM-VAB, 63.8% for IMI-REL), followed by LATAM (65.1% for CAZ-AVI, 70.6% for MEM-VAB, 62.8% for IMI-REL), E-EU (66.6% for CAZ-AVI, 46.7% for MEM-VAB, 43.5% for IMI-REL), and APAC (39.9% for CAZ-AVI, 37.8% for MEM-VAB, 27.7% for IMI-REL). The most common CPE types overall were KPC (44.5% of CREs), NDM (29.8%), and OXA-48-like (16.0%). KPC predominated in LATAM (64.1%) and W-EU (61.1% of CREs). MBL occurrence was highest in APAC (59.5% of CREs), followed by LATAM (34.0%), E-EU (28.9%), and W-EU (23.6%). NDM represented 85.4% of MBLs. Conclusion ATM-AVI demonstrated potent activity against CRE isolates resistant to CAZ-AVI, MEM-VAB, and/or IMI-REL independent of the CPE produced. The activity of recently approved BLIs varied broadly among regions and were very limited in E-EU and APAC. Disclosures Helio S. Sader, MD, PhD, FIDSA, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|bioMerieux: Grant/Research Support|Cipla: Grant/Research Support|CorMedix: Grant/Research Support|Entasis: Grant/Research Support|Melinta: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Leonard R. Duncan, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|CorMedix: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support John H. Kimbrough, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Cecilia G. Carvalhaes, MD, PhD, AbbVie: Grant/Research Support|bioMerieux: Grant/Research Support|Cipla: Grant/Research Support|CorMedix: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support Rodrigo E. Mendes, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Entasis: Grant/Research Support|GSK: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support

2149. In vitro Activity of Aztreonam-avibactam and Comparator Agents Against Carbapenem-Resistant Enterobacterales With and Without Carbapenemases, ATLAS Global Surveillance Program, 2017–2021

Abstract Background The investigational β-lactam/non-β-lactam β-lactamase inhibitor combination aztreonam-avibactam (ATM-AVI) is active in vitro against CRE isolates, including MBL-producers, as well as those co-producing serine β-lactamases of Class A, C, and some class D types. This study evaluated the in vitro activity of ATM-AVI and comparators against carbapenemase- and non-carbapenemase-producing CRE collected globally from 2017−2021 as part of the ATLAS surveillance program. Methods 85,990 non-duplicate, clinically relevant Enterobacterales isolates were collected from 258 medical centers located in 56 countries worldwide (excluding N. America and China). Susceptibility testing was performed by CLSI broth microdilution and interpreted using CLSI 2023 breakpoints. ATM-AVI was tested at a fixed concentration of 4 mg/L avibactam. A tentative ATM-AVI pharmacokinetic/pharmacodynamic (PK/PD) susceptible MIC breakpoint of ≤ 8 mg/L was applied for comparison purposes. Organisms with meropenem MIC &amp;gt;1 mg/L and Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, and Proteus mirabilis with aztreonam or ceftazidime MIC &amp;gt;1 mg/L were screened for β-lactamase genes by PCR and Sanger sequencing. Results In total, 5,473 isolates were identified as CRE based on resistance to meropenem. ATM-AVI demonstrated potent in vitro activity against the CRE, with 99.3% of isolates (MIC90, 1 mg/L) inhibited at ≤8 mg/L (Table). ATM-AVI inhibited 99.5% of the carbapenemase-positive CRE, including 99.1% of the MBL-carriers (n=2,375) and 99.8% of serine-carbapenemase carriers (n=2,675) at ≤8 mg/L. Activity was somewhat reduced against the 441 CRE without detected carbapenemases as 96.3% (MIC90, 4 mg/L) of the isolates were inhibited at ≤8 mg/L aztreonam-avibactam. Amikacin was the most active comparator, although &amp;lt; 50% of each subgroup was susceptible at the CLSI breakpoint. Conclusion Based on MIC90 values and the preliminary PK/PD breakpoint, ATM-AVI demonstrated potent in vitro activity against CRE, including MBL- and serine carbapenemase-carrying isolates. As limited therapeutic options presently exist for treating infections caused by CRE, further development of this agent appears warranted. Disclosures Mark G Wise, PhD, Merck &amp; Co., Inc.: Honoraria|Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation Daniel F. Sahm, PhD, Merck &amp; Co., Inc.: Honoraria|Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation