This study evaluated meropenem-vaborbactam (MVB) pharmacokinetic-pharmacodynamic (PK/PD) in patients with renal dysfunction and continuous renal replacement (CRRT). Eighteen patients (54% female, 17% CRRT) aged 54 ± 14 years, weighing 91 ± 31 kg with a CrCL of 114 ± 102 mL/min/1.73 m2 at baseline, contributed 83 plasma samples. For each drug, a one-compartment PK model was identified. Non-CRRT and residual clearance of meropenem (MEM) was higher than vaborbactam (VAB), resulting in VAB accumulation. Individual-patient target attainment was variable. MEM PTA was >90% at MICs up to 0.5 mg/L, and VAB PTA was >90% at MICs up to 4 mg/L across renal states. CFR for MEM was >80%, and CFR for VAB was >70% in patients with renal dysfunction or CRRT and standard PK/PD targets with renal dosing regimens. For infections with MICs up to 1 mg/L, MVB regimens of 2 g IV every 8 h were adequate in CRRT.

A total of 2036 isolates (1/patient) were consecutively collected from patients with intra-abdominal infections (IAI) in 63 US hospitals in 2019–2023 and susceptibility tested by broth microdilution. Carbapenem-resistant Enterobacterales (CRE) were screened for carbapenemases by whole genome sequencing. The most common Enterobacterales species were E. coli (47.1%), K. pneumoniae (18.7%), and E. cloacae species complex (9.8%). The most active agents were aztreonam-avibactam (MIC50/90, ≤0.03/0.12 mg/L), ceftazidime-avibactam (MIC50/90, 0.12/0.25 mg/L), and meropenem-vaborbactam (MIC50/90, 0.03/0.06 mg/L) with 99.9% susceptibility. A multidrug-resistant (MDR) phenotype (nonsusceptibility to ≥3 classes) was observed in 21.4% of Enterobacterales (n = 436). Piperacillin-tazobactam was active against 87.2% of Enterobacterales overall and 50.2% of MDR isolates, and meropenem was active against 99.2% of Enterobacterales and 96.1% of MDR isolates. Only 51.6% of Enterobacterales were susceptible to ampicillin-sulbactam. An acquired broad-spectrum β-lactamase gene was identified in 207 (10.2%) isolates and included extended-spectrum β-lactamases (ESBL; n = 182), transferable AmpC (n = 24) and carbapenemases (n = 9). Eight isolates produced two β-lactamase classes. Aztreonam-avibactam, ceftazidime-avibactam, and meropenem-vaborbactam exhibited almost complete activity (99.9% susceptibility) against Enterobacterales causing IAI in US hospitals. In contrast, piperacillin-tazobactam exhibited limited activity against these organisms, especially those with a MDR phenotype.

This study evaluated the activity of aztreonam-avibactam and comparator antimicrobial agents against Enterobacterales isolates producing common β-lactamases collected in US hospitals. A total of 18,148 Enterobacterales isolates collected during 2020–2021 in US hospitals (n=71) were susceptibility tested by reference broth microdilution methods. A total of 2,337 isolates were submitted to whole genome sequencing due to elevated cephalosporins/aztreonam MIC values or carbapenem nonsusceptibility (meropenem and/or imipenem MIC results at >1 mg/L). ESBL enzymes were observed among 1,430 carbapenem-susceptible E. coli, K. pneumoniae, E. cloacae and Citrobacter spp. isolates and CTX-M-15 was the most common ESBL. Ceftazidime-avibactam inhibited all ESBL-producers while ceftolozane-tazobactam inhibited 68.4-95.9%. Aztreonam-avibactam inhibited >99.7% of the isolates regardless of the ESBL type or organism. Among other classes, amikacin and tigecycline were the most active agents, inhibiting 78.5% and 97.8% of the ESBL-producing isolates. All isolates carrying transferrable AmpC genes were susceptible to ceftazidime-avibactam and meropenem-vaborbactam, and 98.1% susceptible to aztreonam-avibactam, but only 83.3% were susceptible to ceftolozane-tazobactam. Five isolates carried blaCMY-42 with a PBP3 insertion and they exhibited aztreonam-avibactam MICs ranging from 2-16 mg/L. Among carbapenemase-producers (n=157), aztreonam-avibactam, ceftazidime-avibactam and meropenem-vaborbactam susceptibility rates were 98.7%, 81.5% and 79.6%. The only comparator displaying activity against these isolates was tigecycline (93.0% susceptible). New β-lactam/β-lactamase inhibitors were active against common β-lactamase-producing isolates from US hospitals, including carbapenemase-producing isolates for which therapeutic options are limited. Aztreonam-avibactam was the most active agent against carbapenemase producers, including MBL-carrying isolates.

Determined the activity of cefiderocol (CFD) against 101 Peruvian Pseudomonas aeruginosa isolates. The MIC of CFD ranged from ≤ 0.06 to 8 mg/L (one isolate). CFD resistance rates were 1.0% (according to the FDA and EUCAST) and 0% according to CLSI, whereas 14.9% and 1.0% of isolates were classified as cefiderocol-intermediate according to FDA and CLSI, respectively. CTX-M-131 and GES, and IMP and VIM were the most frequent ESBLs and carbapenemases, respectively. The presence of oprD mutations was tested in 47 carbapenem-resistant isolates, 23 with oprD-inactivating mutations as the sole underlying mechanism. Although no specific association was found between the presence of ESBLs and carbapenemases with CFD resistance, carbapenemase-producing isolates tended to present slightly higher CFD MIC values. The cefiderocol-resistant isolate did not present ESBLs or carbapenemases, showing only an oprD-inactivating mutation. CFD showed excellent activity against P. aeruginosa, irrespective of the presence of ESBLs and/or carbapenemases. The high number of isolates bordering cefiderocol-resistant levels suggests the need for cautious use and continuous surveillance of this antibiotic.

This was a pre-post quasi-experimental study on adult patients with documented KPC-Kp who were treated with ceftazidime/avibactam according to a multidisciplinary approach in the period 1 March 2021–31 October 2024 and patients receiving standard management with ceftazidime/avibactam in the period 1 January 2018–28 February 2021. This study was performed to assess the impact of a multidisciplinary approach aimed at attaining aggressive joint pharmacokinetic/pharmacodynamic (PK/PD) target with ceftazidime/avibactam on treatment outcome of KPC-Klebsiella pneumoniae (Kp) infections and prevention of ceftazidime/avibactam resistance development. Multivariate analysis was performed to identify variables associated with microbiological failure and 90-day resistance development to ceftazidime/avibactam in both pre- and post-intervention phases. A total of 116 and 102 patients in pre- and post-intervention phases were included. A significantly lower microbiological eradication rate (53.0% vs. 81.0%; P < 0.001), a lower clinical cure rate (48.3% vs. 70.6%; P < 0.001), and a higher rate of 90-day resistance development (15.5% vs. 5.9%; P = 0.02) were found in the pre-intervention phase. Continuous renal replacement therapy and a ceftazidime/avibactam MIC value ≥ 4 mg/L emerged as independent predictors of microbiological failure in the pre-intervention phase. Attaining aggressive joint PK/PD target and bloodstream infections resulted in protection against microbiological failure in the post-intervention phase. Attaining aggressive joint PK/PD targets resulted in protection against 90-day resistance development in the post-intervention phase. Implementing a multidisciplinary approach for maximizing the attainment of aggressive joint PK/PD targets of ceftazidime/avibactam could represent an effective strategy for preventing resistance development to ceftazidime/avibactam in KPC-Kp infections.

The Study for Monitoring Antimicrobial Resistance Trends (SMART) surveillance program tested imipenem/relebactam (IMR) and comparators against a total of 2,258 non-duplicate clinical isolates of Enterobacterales (Klebsiella pneumoniae and Escherichia coli) collected across six Brazilian cities during 2020–2021. Antimicrobial susceptibility was determined by the Clinical and Laboratory Standards Institute (CLSI) reference broth microdilution method and interpreted following Brazilian Committee on Antimicrobial Susceptibility (BrCAST)/European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints. Enterobacterales isolates were screened for β-lactamase genes (bla) by sequencing. The most frequent isolates identified among Enterobacterales were E. coli (n = 471; 20.9%) and K. pneumoniae (n = 453; 20.1%). Susceptibility testing showed that >99% of E. coli isolates were susceptible to colistin ([COL], n = 470; 99.8%), meropenem ([MEM], n = 468; 99.4%), IMR (n = 468; 99.4%), and ceftazidime/avibactam ([CZA], n = 468; 99.4%), whereas a high proportion of E. coli multidrug-resistant (MDR) isolates were susceptible to COL (n = 69; 98.6%), CZA (n = 67; 95.7%), MEM (n = 67; 95.7%), IMR (n = 67; 95.7%), and amikacin ([AMK], n = 66; 94.3%). Overall, K. pneumoniae isolates were most susceptible to CZA (n = 414; 91.4%) and IMR (n = 411; 90.7%) and over 86.0% of K. pneumoniae MDR isolates were susceptible to CZA (n = 268; 87.3%) and IMR (n = 265; 86.3%). This study reported that IMR was one of the most effective in vitro β-lactam–β-lactamase inhibitor combinations tested and demonstrated comparable activity to CZA and higher activity than COL against both the Enterobacterales species tested.

In this study, molecular mechanisms contributing to delafloxacin resistance in Pseudomonas aeruginosa strains were investigated. A total of 52 P. aeruginosa strains were collected from clinical isolates. Antimicrobial susceptibility testing was performed via broth microdilution, and the minimum inhibitory concentration (MIC) values for ciprofloxacin, levofloxacin, delafloxacin, ceftazidime and imipenem were determined. Five delafloxacin-resistant P. aeruginosa strains were selected for whole-genome sequencing (WGS). MIC50 values were determined, and the following results were obtained: ciprofloxacin 0.25 mg/L, levofloxacin 0.25 mg/L and delafloxacin 1 mg/L. All five selected strains showed both extended-spectrum beta-lactamase and carbapenemase production. WGS analysis of these strains determined the sequence types (STs), namely, ST235 (two strains), ST316 (two strains) and ST395. Several mutations in quinolone-resistance-determining regions (QRDRs) were detected in all five delafloxacin-resistant P. aeruginosa strains as follows: gyrA Thr83Ile and parC Ser87Leu mutations were present in all five strains, while parE Thr223Ala in ST235, Glu459Val in ST316 and Val200Met in ST395 were detected. MexAB-OprM and MexCD-OprJ efflux pumps were uniformly present in all delafloxacin-resistant P. aeruginosa strains. All strains of ST235 and ST316 carried blaNDM-1 in combination with other beta-lactamases. In this study, the in vitro efficacy of delafloxacin is inferior compared to previous fluoroquinolones based on MIC50 values; however, MIC values of delafloxacin ranged between 0.125 and 128 mg/L in our P. aeruginosa collection, and 21 out of 52 strains showed susceptibility to delafloxacin. Multiple QRDR mutations combined with several efflux pumps confer delafloxacin resistance in P. aeruginosa. Among the different detected multidrug-resistant P. aeruginosa strains in this study, an NDM-1 producing P. aeruginosa ST316 was reported in Hungary.

Retrospective single-arm cohort study of 27 adult patients with SAB who received at least one dose of oritavancin within the Hunter New England Local Health District (HNELHD) between January 2020 and July 2023 was conducted to assess the outcomes, including safety and impact on length of stay and cost-effectiveness of using oritavancin for patients with Staphylococcus aureus bacteraemia (SAB) who are ineligible for outpatient parental antibiotic therapy (OPAT).Among the patients 59% were people who inject drugs, and the sources/ foci of infection included bone/joint infection (26%), skin/ soft tissue infection (15%), infective endocarditis (26%), catheter-associated bacteraemia (CABSI) (7%) and bacteraemia with no clear source/focus (26%). Intravenous antibiotics were administered for a mean duration of 10 days prior to oritavancin therapy. Clinical cure was seen in 26/27 (96%) of patients, with 1 patient lost to follow up and deemed not clinically evaluable (NCE). 24/27 (89%) patients were alive at the end of the 180-day follow-up period, with 2 patient deaths unrelated to their index infection and 1 patient NCE. 89% of patients demonstrated a positive return on investment (ROI), with on average 18 hospitals days per patient avoided. Oritavancin is promising as a suitable and potentially cost-effective alternative for patients with SAB who are ineligible for OPAT. Prospective studies are required to confirm its utility in clinical practice, in particular in patients who do not receive oral antibiotic stepdown therapy.

This comparative effectiveness study assessed the effectiveness of long acting lypoglycopeptides /(laLGP), such as dalbavancin or oritavancin, in managing serious bacterial infections in both people who use drugs (PWUD) and non-PWUD populations compared with standard-of-care (SOC) antibiotics. The study used a target trial emulation framework including data extracted from the US Cerner Real World Data platform. The primary outcome measure was a composite of readmission, emergency department visit, and inpatient death or discharge to hospice within 90 days post discharge from the index admission. Among 42 067 included individuals, median age was 61 (IQR, 47-73) years, 24 704 were male (58.7%), and 5047 (12.0%) were classified as PWUD. laLGPs were prescribed to 825 individuals (2.0%). There was no statistically significant difference in the composite outcome between the laLGP and SOC groups in both the PWUD (HR, 1.01; 95% CI, 0.88-1.13) and non-PWUD (HR, 0.93; 95% CI, 0.86-1.00) participants. In this study of laLGPs vs SOC, findings suggested that laLGPs were effective as step-down treatment of serious gram-positive bacterial infections, offering comparable outcomes to those of SOC antibiotics in PWUD and non-PWUD individuals. Clinicians may consider laLGPs as alternative step-down options to SOC antibiotics for the treatment of serious gram-positive bacterial infections.

Left Ventricular Assist Device (LVAD) utility in heart failure patients is growing and rates of LVAD- related infections remain high limiting outcomes. Authors aimed to assess the effectiveness and safety of oritavancin (ORI) for LVAD-related Gram-positive infections. A retrospective study evaluating adult LVAD patients who received ≥ 1 ORI dose for treatment of Gram-positive LVAD-related infection between Sept 2022 and Dec 2024. The primary endpoint was a 90-day clinical and microbiological cure of primary or relapsing infection within 90 days from the first oritavancin dose. Nine patients were included; all were male, mean age was 53± 9 years. In total they experienced 10 LVAD- related episodes. Most episodes (80%) were deep drive-line infections. Organism most commonly responsible for infection was S. aureus. ORI was administered after a median time of 31 ±13 days of standard antibiotic therapy. In total 18 doses of ORI were administered with median of 2 per case separated on average by 20±4 days. Primary endpoint was achieved in 90% of cases, shortening therapy by a median time of 24 days. Serious adverse events occurred in two out of 9 patients: delirium and shiver with marked increase of inflammatory markers. ORI has a potential to shorten in hospital therapy and improve outcomes in LVAD-related Gram-positive infections in advanced heart failure patients. The study is the first to report delirium and transient increase in inflammatory biomarkers as side effects.

This study aimed to systematically and scientifically investigate the potential associations between the use of fluoroquinolone antibiotics (ciprofloxacin, levofloxacin, moxifloxacin, ofloxacin, norfloxacin, and delafloxacin) and suicidal thoughts and behaviors using data from the Food and Drug Administration Adverse Event Reporting System (FAERS) database. A total of 737 cases of suicidal thoughts and behaviors associated with fluoroquinolones (FQs) were reported in the FAERS database during the study period. Overall, FQs did not demonstrate a disproportionate increase in overall cases of suicidal thoughts and behaviors (ROR: 0.74, 95% CI: 0.69-0.79, P < 0.001; EBGM05 [empirical Bayes geometric mean]: 0.69). The analysis of reported cases of suicidal thoughts and behaviors in the FAERS database does not indicate an overall safety signal associated with fluoroquinolones (FQs) at present.

The objective of this meta-analysis is to determine whether a short course (≤5 days) of fluoroquinolone treatment is as effective as a long course (7 days) in the treatment of patients with an acute exacerbation of chronic obstructive pulmonary disease (COPD). The studies considered eligible for inclusion were randomized trials of antibiotic intervention involving adult patients >18 years of age with a diagnosis of acute exacerbation of COPD, no antimicrobial at the time of the diagnosis and who received treatment with fluoroquinolones in 2 different course duration. The primary outcome analysed was the clinical cure rate at early follow-up in an intention-to-treat. Nine studies with a total of 3951 patients met the inclusion criteria. The methodological quality of the study was high or very high with >77% of the studies having a Jadad score of at least 4. At early (<21 days) and late follow-up, there was no significant difference in clinical cure between the short course of fluoroquinolones therapy and the conventional course. Similar results were found for both antibiotic regimens regarding bacteriologic clearance. Short course was not inferior to the long course when using the same quinolone and it had significantly reduced adverse effects. A short course of fluoroquinolones proved to be as effective as and safer than conventional course in the treatment of patients diagnosed with acute exacerbation of COPD.

This retrospective study was conducted to describe the real-world use of dalbavancin in children under 18 years of age admitted to 3 referral University hospitals in Spain until Jun 30, 2024. Fifteen patients were included, 66% male, with a median age of 7.1 years. The most common infection was endocarditis (4, 26%) and endovascular infections (3, 20%), and the most frequently isolated microorganism was S. aureus (9, 60%). The main reason to use dalbavancin was for consolidation treatment (15, 100%) to facilitate earlier hospital discharge (11, 73.3%). Dalbavancin was administered in one-dose regimen in 8 patients (53.3%), in two-dose regimen in 5 patients (30%) and multiple-dose regimen in 2 cases (13.3%). One patient developed macular rash and diarrhoea and dalbavancin was discontinued. Fourteen patients (93%) were cured of infection at day 90. Dalbavancin could be considered as a consolidation treatment for severe infections caused by gram-positive microorganisms. It appears to be safe and effective in most children. A better understanding of the pharmacokinetics of dalbavancin in multiple-dose regimens is of special interest.