UNASSIGNED: Infections caused by Acinetobacter baumannii, particularly those resistant to antibiotics such as carbapenem, have become a global health crisis with a significant mortality rate. Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) resulting from the A. baumannii-calcoaceticus (ABC) complex represent a major clinical challenge. This review aimed to understand the approval process, mechanism of action, therapeutic potential, and future implications of sulbactam-durlobactam therapy (SUL-DUR).
UNASSIGNED: PubMed, Web of Science, EMBASE, Clinical trials. gov, ICTRP, and CENTRAL were searched for studies on SUL-DUR for the treatment of hospital-acquired pneumonia and ventilator-associated pneumonia. Also, World Health Organization, U.S. Food and Drug Administration, and Centers for Disease Control and Prevention websites were searched for relevant information.
UNASSIGNED: SUL-DUR, marketed as Xacduro, is a novel pharmaceutical combination that functions as a narrow-spectrum parenterally administered antibiotic. Sulbactam acts as a β-lactamase inhibitor, whereas durlobactam protects against degradation by A. baumannii enzymes. A phase 1 trial successfully established the safety and tolerability of SUL-DUR in patients with normal and mild renal impairment. A phase 2 trial demonstrated the safety and tolerability of SUL-DUR in a larger population with urinary tract infections. A phase 3 trial showed that SUL-DUR was non-inferior to colistin in terms of mortality in A. baumannii-related VAP, HAP, and bacteremia.
UNASSIGNED: The combination of sulbactam and durlobactam is a promising treatment option for HAP and VAP caused by ABC complex.

UNASSIGNED: Infections with Acinetobacter baumannii-calcoaceticus complex (ABC) pose difficulty for clinicians given a limited arsenal of effective antimicrobials. Sulbactam/durlobactam provides a novel treatment option for patients experiencing hospital- or ventilator-acquired pneumonia with susceptible strains.
UNASSIGNED: This review provides a comprehensive discussion of sulbactam/durlobactam, including basic characteristics, in vitro activity, and clinical trial data supporting its use for the treatment of ABC. Manufacturer\'s data, published literature to date, and conference data are utilized in this review.
UNASSIGNED: Sulbactam/durlobactam offers clinicians a new and effective treatment option for resistant ABC infection. Sulbactam, when combined with durlobactam, displays enhanced potency against ABC isolates, which has translated into positive clinical outcomes observed in clinical trials and post-marketing case studies. Although overall treatment indications and clinical experience are limited to date, sulbactam/durlobactam offers a familiar and favorable safety profile in comparison with alternative agents. Factors associated with use of combination antibiotic therapy, availability of commercial drug susceptibility testing, and cost-effectiveness are all currently key considerations for sulbactam/durlobactam use.

BACKGROUND: Glycopeptides for ampicillin-susceptible Enterococcus faecalis/faecium bacteremia are readily prescribed depending on the severity of the condition. However, there is limited data on the outcomes of glycopeptide use compared to ampicillin-containing regimens for ampicillin-susceptible E. faecalis/faecium bacteremia. From an antibiotic stewardship perspective, it is important to determine whether the use of glycopeptides is associated with improved clinical outcomes in patients with ampicillin-susceptible E. faecalis/faecium bacteremia.
METHODS: This retrospective cohort study was conducted at a university-affiliated hospital between January 2010 and September 2019. We collected data from patients with positive blood cultures for Enterococcus species isolates. The clinical data of patients who received ampicillin-containing regimens or glycopeptides as definitive therapy for ampicillin-susceptible E. faecalis/faecium bacteremia were reviewed. Multivariate logistic regression analysis was performed to identify risk factors for 28-day mortality.
RESULTS: Ampicillin-susceptible E. faecalis/faecium accounted for 41.2% (557/1,353) of enterococcal bacteremia cases during the study period. A total of 127 patients who received ampicillin-containing regimens (N = 56) or glycopeptides (N = 71) as definitive therapy were included in the analysis. The 28-day mortality rate was higher in patients treated with glycopeptides (19.7%) than in those treated with ampicillin-containing regimens (3.6%) (p = 0.006). However, in the multivariate model, antibiotic choice was not an independent predictor of 28-day mortality (adjusted OR, 3.7; 95% CI, 0.6-23.6).
CONCLUSIONS: Glycopeptide use was not associated with improved mortality in patients with ampicillin-susceptible E. faecalis/faecium bacteremia. This study provides insights to reduce the inappropriate use of glycopeptides in ampicillin-susceptible E. faecalis/faecium bacteremia treatment and promote antimicrobial stewardship.

We investigated the activity of cefiderocol/β-lactamase inhibitor combinations against clinical strains with different susceptibility profiles to cefiderocol to explore the potentiality of antibiotic combinations as a strategy to contain the major public health problem of multidrug-resistant (MDR) pathogens. Specifically, we evaluated the synergistic activity of cefiderocol with avibactam, sulbactam, or tazobactam on three of the most \"Critical Priority\" group of MDR bacteria (carbapenem-resistant Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii). Clinical isolates were genomically characterized by Illumina iSeq 100. The synergy test was conducted with time-kill curve assays. Specifically, cefiderocol/avibactam, /sulbactam, or /tazobactam combinations were analyzed. Synergism was assigned if bacterial grow reduction reached 2 log10 CFU/mL. We reported the high antimicrobial activity of the cefiderocol/sulbactam combination against carbapenem-resistant Enterobacterales, P. aeruginosa, and A. baumannii; of the cefiderocol/avibactam combination against carbapenem-resistant Enterobacterales; and of the cefiderocol/tazobactam combination against carbapenem-resistant Enterobacterales and P. aeruginosa. Our results demonstrate that all β-lactamase inhibitors (BLIs) tested are able to enhance cefiderocol antimicrobial activity, also against cefiderocol-resistant isolates. The cefiderocol/sulbactam combination emerges as the most promising combination, proving to highly enhance cefiderocol activity in all the analyzed carbapenem-resistant Gram-negative isolates, whereas the Cefiderocol/tazobactam combination resulted in being active only against carbapenem-resistant Enterobacterales and P. aeruginosa, and cefiderocol/avibactam was only active against carbapenem-resistant Enterobacterales.

Cefiderocol, a siderophore-cephalosporine conjugate antibiotic, shows promise as a therapeutic option for carbapenem-resistant (CR) Acinetobacter infections. While resistance has already been reported in A. baumannii, combination therapies with avibactam or sulbactam reduce MICs of cefiderocol, extending its efficacy. However, careful consideration is necessary when using these combinations. In our experiments, exposure of A. baumannii and A. lwoffii to cefiderocol and sulbactam or avibactam led to the selection of cefiderocol-resistant strains. Three of those were subjected to whole genome sequencing and transcriptomic analysis. The strains all possessed synonymous and non-synonymous substitutions and short deletions. The most significant mutations affected efflux pumps, transcriptional regulators, and iron homeostasis genes. Transcriptomics showed significant alterations in expression levels of outer membrane proteins, iron homeostasis, and β-lactamases, suggesting adaptive responses to selective pressure. This study underscores the importance of carefully assessing drug synergies, as they may inadvertently foster the selection of resistant variants and complicate the management of CR Acinetobacter infections.IMPORTANCEThe emergence of carbapenem-resistant Acinetobacter strains as a serious global health threat underscores the urgent need for effective treatment options. Although few drugs show promise against CR Acinetobacter infections, resistance to both drugs has been reported. In this study, the molecular characterization of spontaneous cefiderocol-resistant variants, a CR A. baumannii strain with antagonism to sulbactam, and an A. lwoffii strain with antagonism to avibactam, provides valuable insights into the mechanisms of resistance to cefiderocol. Some mechanisms observed are associated with mutations affecting efflux pumps, regulators, and iron homeostasis genes. These findings highlight the importance of understanding resistance mechanisms to optimize treatment options. They also emphasize the importance of early evaluation of drug synergies to address the challenges of antimicrobial resistance in Acinetobacter infections.

OBJECTIVE: Sulbactam (SBT) is one of the most significant treatments for patients with extensively drug-resistant Acinetobacter baumannii (XDR-AB). However, the efficacy and safety of SBT and its high dose regimen has not been well documented. This retrospective study aimed to assess the efficacy and safety of SBT-based treatment, particularly at high-dose (≥ 6 g/day), for XDR-AB infection.
METHODS: A total of 52 XDR-AB infected patients treated with intravenous SBT at Peking Union Medical College Hospital were included. The primary outcome was 28-day all-cause mortality, while the secondary outcome was 14-day clinical response and the time of response. The formulation of SBT in our study is 0.5 g per vial.
RESULTS: Among the patients, the 28-day all-cause mortality rate was 36.5% (19/52), and the favorable 14-day clinical response rate was 59.6% (31/52). The 28-day mortality was independently associated coinfection with gram-positive bacteria (GPB) and a shorter duration of therapy. Patients with intracranial infection might have a longer survival time. A favorable 14-day clinical response was associated with the dose of SBT, and a longer treatment duration. However, the higher creatinine clearance (CrCl) associated with a worse clincal response. In addition, a higher SBT dosage was significantly correlated with a shorter time to clinical response. No adverse effects related were reported.
CONCLUSIONS: The single-agent formulation of SBT emerges as a promising alternative for the treatment of XDR-AB infection, such as intracranial infection, particularly at high doses (≥ 6 g/day). Besides, longer duration of treatment correlates with higher survival rate and better favorable clinical response. Higher CrCl negatively correlates with favorable clinical response.

BACKGROUND: Sulbactam dosing for Acinetobacter baumannii infections has not been standardized due to limited available pharmacokinetics/pharmacodynamics (PK/PD) data. Herein, we report a comprehensive PK/PD analysis of ampicillin-sulbactam against A. baumannii pneumonia.
METHODS: Twenty-one A. baumannii clinical isolates were tested in the neutropenic murine pneumonia model. For dose-ranging studies, groups of mice were administered escalating doses of ampicillin-sulbactam. Changes in log10cfu/lungs relative to 0 h were assessed. Dose-fractionation studies were performed. Estimates of the percentage of of time during which the unbound plasma sulbactam concentrations exceeded the MIC (%fT > MIC) required for different efficacy endpoints were calculated. The probabilities of target attainment (PTA) for the 1-log kill plasma targets were estimated following clinically utilized sulbactam regimens.
RESULTS: Dose-fractionation studies demonstrated time-dependent kill. Isolates resistant to both sulbactam and meropenem required three times the exposures to achieve 1-log kill; median [IQR] %fT > MIC of 60.37% [51.6-66.8] compared with other phenotypes (21.17 [16.0-32.9] %fT > MIC). Sulbactam standard dose (1 g q6h, 0.5 h infusion) provided >90% PTA up to MIC of 4 mg/L. Sulbactam 3 g q8h, 4 h inf provided greater PTA for isolates with sulbactam-intermediate susceptibility (8 mg/L, 100% versus 86% following the standard dose). Despite the higher exposure following 3 g q8h, 4 h inf, PTA was ≤57% among sulbactam-resistant/meropenem-resistant isolates.
CONCLUSIONS: Sulbactam standard dose is a valuable regimen across sulbactam-susceptible isolates while the high-dose extended-infusion provides additional benefit against sulbactam-intermediate isolates. Given that most of the sulbactam-resistant A. baumannii isolates are meropenem-resistant, high-dose prolonged-infusion regimens are not expected to be effective as monotherapy against infections due to these isolates.

Carbapenem-resistant Acinetobacter baumannii (CRAB) is a Priority 1 (Critical) pathogen urgently requiring new antibiotics. Polymyxins are a last-line option against CRAB-associated infections. This transcriptomic study utilized a CRAB strain to investigate mechanisms of bacterial killing with polymyxin B, colistin, colistin B, and colistin/sulbactam combination therapy. After 4 h of 2 mg/L polymyxin monotherapy, all polymyxins exhibited common transcriptomic responses which primarily involved disruption to amino acid and fatty acid metabolism. Of the three monotherapies, polymyxin B induced the greatest number of differentially expressed genes (DEGs), including for genes involved with fatty acid metabolism. Gene disturbances with colistin and colistin B were highly similar (89 % common genes for colistin B), though effects on gene expression were generally lower (0-1.5-fold in most cases) with colistin B. Colistin alone (2 mg/L) or combined with sulbactam (64 mg/L) resulted in rapid membrane disruption as early as 1 h. Transcriptomic analysis of this combination revealed that the effects were driven by colistin, which included disturbances in fatty acid synthesis and catabolism, and inhibition of nutrient uptake. Combination therapy produced substantially higher fold changes in 72 % of DEGs shared with monotherapy, leading to substantially greater reductions in fatty acid biosynthesis and increases in biofilm, cell wall, and phospholipid synthesis. This indicates synergistic bacterial killing with the colistin/sulbactam combination results from a systematic increase in perturbation of many genes associated with bacterial metabolism. These mechanistic insights enhance our understanding of bacterial responses to polymyxin mono- and combination therapy and will assist to optimize polymyxin use in patients.

OBJECTIVE: The use of cefoperazone/sulbactam (CPZ/SAM) could commonly cause vitamin K-dependent coagulation disorders and even hemorrhage sometimes. However, there is a lack of prediction tools estimating the risk for this. This study aimed at developing and internally validating a model for predicting CPZ/SAM-associated coagulation disorders in Chinese inpatients.
METHODS: A case-control study was conducted in 11,092 adult inpatients admitted to a Chinese general hospital between 2020 and 2021 and treated with CPZ/SAM. Patients with CPZ/SAM-associated coagulation disorders were identified through the Adverse Drug Events Active Surveillance and Assessment System-II and subsequent manual evaluation. Controls were selected from eligible patients who didn\'t develop coagulation disorders after CPZ/SAM therapy, with a 1:1 propensity score matching. The final predictors were obtained by univariable and multivariable logistic regression analyses. Internal validation and calibration for the model were performed using 1000 bootstrap resamplings.
RESULTS: 258 patients were identified as CPZ/SAM-associated coagulation disorders in 2184 patients eligible for inclusions and exclusions and the incidence was 11.8%. A final population of 252 cases and 252 controls was included for model development and validation. Malnutrition (OR = 2.41 (1.56-3.77)), history of recent bleeding (OR = 1.95 (1.32-2.90)), treatment duration (OR = 1.10 (1.07-1.14)), combination with carbapenems (OR = 4.43 (1.85-11.88)), and serum creatinine (OR = 1.01 (1.00-1.01)) were identified as final predictors. The model showed good discrimination, calibration, and clinical practicality, with the validated area under the receiver operating characteristic curve being 0.723 (0.683-0.770).
CONCLUSIONS: The model with good performance quantifies the risk for CPZ/SAM-associated coagulation disorders, and may support individual assessment and interventions to mitigate the risk after external validation.

OBJECTIVE: We evaluated the efficacies of human-simulated regimens (HSRs) of two clinically utilized sulbactam regimens: 1 g q6h 0.5 h infusion (maximum FDA-approved dosage) and 3 g q8h 4 h infusion (high-dose, prolonged-infusion regimen), against Acinetobacter baumannii in a translational murine model.
METHODS: Thirty-two clinical A. baumannii isolates were investigated, of which 16 were sulbactam resistant (MIC ≥ 16 mg/L), 6 were sulbactam intermediate (MIC = 8 mg/L) and 10 were sulbactam susceptible (MIC ≤ 4 mg/L). Efficacies of the two sulbactam HSRs were assessed in the neutropenic murine pneumonia model. Changes in log10 cfu/lungs at 24 h compared with 0 h controls were measured, and efficacy was defined as achieving 1 log kill relative to baseline. WGS of the isolates and bioinformatics analysis were performed to explore potential associations between the genomic backgrounds and the in vivo responses.
RESULTS: Eleven isolates harboured blaOXA-23, of which 10 were sulbactam resistant, 1 was sulbactam intermediate while none was sulbactam susceptible. Both sulbactam HSRs achieved >1 log kill against sulbactam-susceptible isolates. Against sulbactam-intermediate and sulbactam-resistant isolates, lack of efficacy correlated with the presence of the blaOXA-23 gene; sulbactam 1 g HSR and 3 g HSR did not show efficacy against 11/11 and 9/11 blaOXA-23-positive isolates, respectively, while efficacy was observed against all 11 blaOXA-23-negative sulbactam-intermediate and sulbactam-resistant isolates (i.e. harbouring other resistance genes).
CONCLUSIONS: A sulbactam high-dose prolonged-infusion regimen provides comparable activity to the standard dose against isolates currently considered sulbactam susceptible. However, the activity against isolates with intermediate and resistant susceptibility could be predicted by the detection of blaOXA-23. Enhancing detection capabilities of common diagnostic modalities to include OXA-23 can improve patient outcome.