Light-activated conjugated polymer nanoparticles to defeat pathogens associated with bovine mastitis.

Bovine mastitis (BM) represents a significant challenge in the dairy industry. Limitations of conventional treatments have prompted the exploration of alternative approaches, such as photodynamic inactivation (PDI). In this study, we developed a PDI protocol to eliminate BM-associated pathogens using porphyrin-doped conjugated polymer nanoparticles (CPN). The PDI-CPN protocol was evaluated in four mastitis isolates of Staphylococcus and in a hyper-biofilm-forming reference strain. The results in planktonic cultures demonstrated that PDI-CPN exhibited a bactericidal profile upon relatively low light doses (∼9.6 J/cm2). Furthermore, following a seven-hour incubation period, no evidence of cellular reactivation was observed, indicating a highly efficient post-photodynamic inactivation effect. The successful elimination of bacterial suspensions encouraged us to test the PDI-CPN protocol on mature biofilms. Treatment using moderate light dose (∼64.8 J/cm2) reduced biofilm biomass and metabolic activity by up to 74% and 88%, respectively. The impact of PDI-CPN therapy on biofilms was investigated using scanning electron microscopy (SEM), which revealed nearly complete removal of the extracellular matrix and cocci. Moreover, ex vivo studies conducted on bovine udder skin demonstrated the efficacy of the therapy in eliminating bacteria from these scaffolds and its potential as a prophylactic method. Notably, the histological analysis of skin revealed no signs of cellular degeneration, suggesting that the protocol is safe and effective for BM treatment. Overall, this study demonstrates the potential of PDI-CPN in treating and preventing BM pathogens. It also provides insights into the effects of PDI-CPN on bacterial growth, metabolism, and survival over extended periods, aiding the development of effective control strategies and the optimization of future treatments.

Activity of Aztreonam/Avibactam and Recently Approved ß-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 ß-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.

Blood-brain barrier biomarkers.

The blood-brain barrier (BBB) is a dynamic interface that regulates the exchange of molecules and cells between the brain parenchyma and the peripheral blood. The BBB is mainly composed of endothelial cells, astrocytes and pericytes. The integrity of this structure is essential for maintaining brain and spinal cord homeostasis and protection from injury or disease. However, in various neurological disorders, such as traumatic brain injury, Alzheimer's disease, and multiple sclerosis, the BBB can become compromised thus allowing passage of molecules and cells in and out of the central nervous system parenchyma. These agents, however, can serve as biomarkers of BBB permeability and neuronal damage, and provide valuable information for diagnosis, prognosis and treatment. Herein, we provide an overview of the BBB and changes due to aging, and summarize current knowledge on biomarkers of BBB disruption and neurodegeneration, including permeability, cellular, molecular and imaging biomarkers. We also discuss the challenges and opportunities for developing a biomarker toolkit that can reliably assess the BBB in physiologic and pathophysiologic states.

An ambipolar PEDOT-perfluorinated porphyrin electropolymer: application as an active material in energy storage systems.

The development of functional organic materials is crucial for the advancement of various fields, such as optoelectronics, energy storage, sensing, and biomedicine. In this context, we successfully prepared a stable ambipolar perfluoroporphyrin-based polymeric film by electrochemical synthesis. Our strategy involved the synthesis of a novel tetra-pentafluorophenyl porphyrin covalently linked to four 3,4-ethylenedioxythiophene (EDOT) moieties. The resulting monomer, EDOT-TPPF16, was obtained through a straightforward synthetic approach with a good overall yield. The unique molecular structure of EDOT-TPPF16 serves a dual function, with EDOT moieties allowing electropolymerization for polymeric film formation, while the electron-acceptor porphyrin core enables electrochemical reduction and electron transport. The electrochemical polymerization permits the polymer (PEDOT-TPPF16) synthesis and film formation in a reproducible and controllable manner in one step at room temperature. Spectroelectrochemical experiments confirmed that the porphyrin retained its optoelectronic properties within the polymeric matrix after the electrochemical polymerization. The obtained polymeric material exhibited stable redox capabilities. Current charge-discharge cycles and electrochemical impedance spectroscopy of the electrochemically generated organic film demonstrated that the polymer could be applied as a promising active material in the development of supercapacitor energy storage devices.

Patient outcomes by baseline pathogen resistance phenotype and genotype in CERTAIN-1, a Phase 3 study of cefepime-taniborbactam versus meropenem in adults with complicated urinary tract infection.

CERTAIN-1 was a Phase 3, double-blind, randomized, parallel group study of the efficacy and safety of cefepime-taniborbactam versus meropenem in the treatment of adults with complicated urinary tract infection (cUTI), including acute pyelonephritis. We determined susceptibility of Enterobacterales and Pseudomonas aeruginosa baseline pathogens to cefepime-taniborbactam and comparators and characterized ß-lactam resistance mechanisms. Microbiologic response and clinical response were assessed in patient subsets defined by baseline pathogens that were of cefepime-, multidrug-, or carbapenem-resistant phenotype or that carried ß-lactamase genes. Among Enterobacterales baseline pathogens, 26.8%, 4.1%, and 3.0% carried genes for extended-spectrum ß-lactamases (ESBLs), AmpC, and carbapenemases, respectively. Within each treatment group, while composite success rates at Test of Cure in resistant subsets by pathogen species were similar to those by pathogen overall, composite success rates in meropenem patients were numerically lower for cefepime-resistant Escherichia coli (9/19; 47.4%) and ESBL E. coli (13/25; 52.0%) compared with E. coli overall (62/100; 62.0%). Cefepime-taniborbactam achieved composite success in 7/8 (87.5%) patients with carbapenem-resistant Enterobacterales and 8/9 (88.9%) patients with Enterobacterales with a carbapenemase gene (5 OXA-48-group; 2 KPC-3; 2 NDM-1). Cefepime-taniborbactam also achieved composite success in 8/16 (50.0%) patients and clinical success in 13/16 (81.3%) patients with P. aeruginosa; corresponding rates were 4/7 (57.1%) and 6/7 (85.7%) for meropenem. Cefepime-taniborbactam demonstrated efficacy in adult cUTI patients with cefepime-, multidrug-, and carbapenem-resistant pathogens including pathogens with ESBL, AmpC, and carbapenemase genes. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT03840148.

Amoxicillin-clavulanate Breakpoints Against Enterobacterales: Rationale for Revision by the Clinical and Laboratory Standards Institute.

Amoxicillin-clavulanate (AMC) is among the most frequently prescribed antibiotics globally. It has broad antibacterial activity against gram-positive, gram-negative, and anaerobic bacteria, and has been utilized to treat infections caused by a broad range of pathogens. AMC breakpoints against Enterobacterales were initially set in the 1980s but since then increases in antibiotic resistance, advances in pharmacokinetic (PK)/pharmacodynamic (PD) analyses, and publication of additional clinical data prompted a reassessment by the Clinical and Laboratory Standards Institute (CLSI) Subcommittee on Antimicrobial Susceptibility Testing. Based on this contemporary reappraisal, the CLSI retained the Enterobacterales breakpoints but revised comments regarding dosing associated with use of the AMC breakpoints in the 2022 supplement of M100. This viewpoint provides insight into the CLSI breakpoint reevaluation process and summarizes the data and rationale used to support these revisions to the AMC Enterobacterales breakpoint.

Specific nanoprobe design for MRI: Targeting laminin in the blood-brain barrier to follow alteration due to neuroinflammation.

Chronic neuroinflammation is characterized by increased blood-brain barrier (BBB) permeability, leading to molecular changes in the central nervous system that can be explored with biomarkers of active neuroinflammatory processes. Magnetic resonance imaging (MRI) has contributed to detecting lesions and permeability of the BBB. Ultra-small superparamagnetic particles of iron oxide (USPIO) are used as contrast agents to improve MRI observations. Therefore, we validate the interaction of peptide-88 with laminin, vectorized on USPIO, to explore BBB molecular alterations occurring during neuroinflammation as a potential tool for use in MRI. The specific labeling of NPS-P88 was verified in endothelial cells (hCMEC/D3) and astrocytes (T98G) under inflammation induced by interleukin 1ß (IL-1ß) for 3 and 24 hours. IL-1ß for 3 hours in hCMEC/D3 cells increased their co-localization with NPS-P88, compared with controls. At 24 hours, no significant differences were observed between groups. In T98G cells, NPS-P88 showed similar nonspecific labeling among treatments. These results indicate that NPS-P88 has a higher affinity towards brain endothelial cells than astrocytes under inflammation. This affinity decreases over time with reduced laminin expression. In vivo results suggest that following a 30-minute post-injection, there is an increased presence of NPS-P88 in the blood and brain, diminishing over time. Lastly, EAE animals displayed a significant accumulation of NPS-P88 in MRI, primarily in the cortex, attributed to inflammation and disruption of the BBB. Altogether, these results revealed NPS-P88 as a biomarker to evaluate changes in the BBB due to neuroinflammation by MRI in biological models targeting laminin.

A comparison of three techniques for the osteosynthesis after minimal invasive osteotomies for hallux valgus.

PURPOSE: Third and fourth-generation minimal invasive osteotomies (MIO) for the treatment of hallux valgus (HV) have become popular procedures worldwide with promising results due to the improvement in the fixation method. The tricortical cannulated screw placement remains a complex procedure that is technically challenging and requires a long skill learning curve with high radiation exposure mainly in the form of intensifier shots (IS) required for the MIO fixation. This study aims to compare the number of X-ray IS required using three different techniques for the cannulated guide placement. METHODS: A retrospective cross-sectional observational and comparative study was conducted to assess the number of X-rays IS required for correct cannulated screw guide placement using three different techniques: traditional perforator, the drill and joystick, and K-wire first techniques. RESULTS: A total of 53 MIS procedures from thirty-one patients in two different hospitals were included. IS X-rays were 155.1 ± 29.7 in the traditional technique (n = 14), 143.0 ± 43.2 in the drill and joystick technique (n = 22), and 85 ± 18.7 in the K-wires first technique (n = 17), p = < 0.001 using one-way ANOVA. CONCLUSIONS: The K-wire first technique statistically significantly decreases X-ray IS numbers p ≤ 0.001. There were no statistically significant differences between the traditional (after osteotomy K-wire placement) and the drill and joystick techniques (p = 0.36).

Proficiency Levels and Validity Evidence for Scoring Metrics for a Virtual Reality and Inanimate Robotic Surgery Simulation Curriculum.

OBJECTIVE: Our institution recently implemented a virtual reality (VR) skills curriculum for general surgery residents using the SimNow simulator. Based on a content alignment study, we revised the curriculum to include only 20 of 33 VR tasks and we added 3 previously validated inanimate tasks. The purpose of this study was to establish expert-derived proficiency levels for all tasks and to evaluate the validity of the scoring for the VR tasks. DESIGN: Two expert robotic surgeons performed 5 repetitions of each VR and inanimate task. The trimmed mean (lowest scoring attempt and outliers [>2 standard deviations] were eliminated) was defined as the expert level for each task. For the VR tasks, expert levels were compared to resident performance to evaluate validity. SETTING: This study was conducted at the University of Texas Southwestern Medical Center (Dallas, TX), a tertiary care academic teaching hospital. PARTICIPANTS: Two expert robotic surgeons participated in this study. The data from 42 residents (PGY2-4) who completed the original curriculum was used to represent novice performance. RESULTS: Comparison of expert levels and resident performance was statistically significant for 15 VR tasks (supporting validity) and approached significance (p = 0.06, 0.09) for 2 VR tasks; expert levels were designated as proficiency levels for these 17 tasks. Group comparisons were clearly not significant (p = 0.2-0.8) for 3 VR tasks; 2 of these 3 tasks were retained as introductory exercises (with 3 repetitions required) and 1 was excluded. For the 3 inanimate tasks, expert levels minus 2 standard deviations were designated as proficiency levels. CONCLUSIONS: This analysis generated validity evidence for 15 VR tasks and established expert-derived proficiency levels for 17 VR tasks and 3 inanimate tasks. Our proposed curriculum now consists of 19 VR and 3 inanimate tasks using the selected proficiency levels. We anticipate that this design will maximize curriculum efficiency and effectiveness.

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).

BACKGROUND: Aztreonam-avibactam is under clinical development for treatment of infections caused by carbapenem-resistant Enterobacterales (CRE), especially those resistant to recently approved ß-lactamase inhibitor combinations (BLICs). OBJECTIVES: To evaluate a large collection of CRE isolates, including those non-susceptible to ceftazidime-avibactam, meropenem-vaborbactam, and/or imipenem-relebactam. METHODS: Overall, 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. RESULTS: Aztreonam-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%). CONCLUSIONS: Aztreonam-avibactam demonstrated potent activity against CRE isolates resistant to ceftazidime-avibactam, meropenem-vaborbactam, and/or imipenem-relebactam independent of the carbapenemase produced.

Intensifying supportive care is associated with improved survival in gastric cancer patients with malignant ascites.

BACKGROUND: Gastric cancer patients with malignant ascites often have poor functional status and malnutrition that preclude receipt of systemic therapies. Thus, these patients have a very poor prognosis. Beginning in 2019, our multidisciplinary gastric cancer disease-oriented team implemented a more aggressive supportive care plan for gastric cancer patients with malignant ascites. The initiative included measures such as supplemental enteral nutrition, ascites drainage, and initiation of chemotherapy on an inpatient basis. We compared outcomes for gastric cancer patients who presented with synchronous malignant ascites treated before and after the implementation of the care plan. METHODS: We performed a retrospective review of our institutional database to identify patients diagnosed with gastric adenocarcinoma and synchronous malignant ascites between 2010 and 2022. We compared overall survival (OS) between patients diagnosed from 2010 to 2018, which will be referred to as the historical control era and patients diagnosed from 2019 to 2022, which will be called the aggressive supportive care era. RESULTS: Fifty-four patients were included in our analysis; 31 patients were treated in the historical control time frame, and 23 patients were treated during the aggressive supportive care era. Demographic, clinical, and pathologic characteristics were similar between groups. 3% of historical controls received supplemental tube feeds at diagnosis as compared to 30% of the aggressive supportive care cohort (p < 0.01). 3% of historical controls received their first cycle of chemotherapy in the inpatient setting versus 39% of patients treated during the aggressive supportive care era (p < 0.01). The median number of chemotherapy cycles received was 5 among historical controls and 9.5 among aggressive supportive care era patients (p = 0.02). There was no difference in the number of days spent as an inpatient between the two groups. The median OS for historical control patients was 5.4 months as compared with 10.4 months for patients treated during aggressive supportive care era (p = 0.04). CONCLUSIONS: Gastric cancer patients with synchronous malignant ascites treated during a timeframe when our multidisciplinary team implemented more aggressive supportive care measures had improved OS as compared with historic controls. Our results suggest that aggressive supportive measures for these patients with highly challenging clinical issues and poor prognosis can prolong survival. Specifically, initiation of chemotherapy in the inpatient setting and supplemental nutrition should be considered for patients at high risk for treatment intolerance.

Evaluation of Different Techniques and Materials for Filling in 3-dimensional Printed Teeth Replicas with Perforating Internal Resorption by Means of Micro-Computed Tomography.

INTRODUCTION: The aim of this study was to evaluate the filling ability of 2 obturation techniques in 3-dimensional (3D) printed teeth with perforating internal resorption (PIR). METHODS: A maxillary central incisor was instrumented and scanned by micro-computed tomographic (micro-CT) imaging. The 3D model was exported in the stereolithographic format and, with the aid of OrtogOnBlender software (Cícero Moraes, Sinop, SP, Brazil), a PIR in the middle third of the root canal was designed. Thirty-two replicas were printed in surgical resin and distributed into 4 groups (n = 8) according to the obturation technique and the material used: 2 groups used the hybrid technique, 1 with Bio-C Sealer (BCS; Angelus, Londrina, PR, Brazil)/gutta-percha (GP; VDW GmbH, Munich, Germany) + Bio-C Repair (BCR; Angelus, Londrina, PR, Brazil) and the other with BioRoot (BR; Septodont, Saint Maur des Fosses, France)/gutta-percha (GP) + Biodentine (BD; Septodont, Saint Maur des Fosses, France), and 2 groups used the incremental technique, 1 with BCR and the other with BD. Postobturation micro-CT imaging was performed to measure the percentage volume of voids and laser confocal microscopy to measure the surface roughness (µm) of the repair cements. Data were compared using analysis of variance and Kruskal-Wallis tests. RESULTS: Regarding the filling volume in the apical third, the BCS/GP + BCR (89.70 ± 5.15), BR/GP + BD (87.70 ± 8.43), and BCR (84.20 ± 9.00) groups showed the highest percentages compared with the BD group (69.70 ± 6.88) (P < .05). In the area of internal resorption, the BCS/GP + BCR (96.00 ± 2.64) and BCR (95.30 ± 2.93) groups showed the highest percentages compared with the BR/GP + BD group (91.50 ± 1.35) (P < .05). The BD group showed intermediate values that were sometimes similar to the BCS/GP + BCR and BCR groups and similar to the BR/GP + BD group (P > .05). Regarding the quality of the filling in the perforation area, the BCR group showed better results compared with the BD group (P < .001). Regarding roughness, the BCR group (1.66 ± 0.65) showed lower surface roughness compared with the BD group (2.51 ± 0.89) (P < .05). CONCLUSIONS: The capacity and quality of the filling in teeth with PIR were superior with the incremental technique with BCR and the hybrid technique with BCS/GP + BCR.

Association of race, demographic and socioeconomic factors with failure to rescue after hepato-pancreato-biliary surgery in the United States.

BACKGROUND: We aimed to describe the association of patient-related factors such as race, socioeconomic status, and insurance on failure to rescue (FTR) after hepato-pancreato-biliary (HPB) surgeries. METHODS: Using the National Inpatient Sample, we analyzed 98,788 elective HPB surgeries between 2004 and 2017. Major and minor complications were identified using ICD9/10 codes. We evaluated mortality rates and FTR (inpatient mortality after major complications). We used multivariate logistic regression analysis to assess racial, socioeconomic, and demographic factors on FTR, adjusting for covariates. RESULTS: Overall, 43 % of patients (n = 42,256) had pancreatic operations, 36% (n = 35,526) had liver surgery, and 21% (n = 21,006) had biliary interventions. The overall major complication rate was 21% (n = 20,640), of which 8% (n = 1655) suffered FTR. Factors independently associated with increased risk for FTR were male sex, older age, higher Charlson Comorbidity Index, Hispanic ethnicity, Asian or other race, lower income quartile, Medicare insurance, and southern region hospitals. CONCLUSIONS: Medicare insurance, male gender, Hispanic ethnicity, and lower income quartile were associated with increased risk for FTR. Efforts should be made to improve the identification and subsequent treatment of complications for those at high risk of FTR.

Cost Analysis and Financial Implications of a Peritoneal Surface Malignancy Program in the USA.

BACKGROUND: We aimed to describe the financial implications of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) in the USA. MATERIALS AND METHODS: We conducted a retrospective cost analysis of 100 CRS/HIPEC procedures to examine the impact of patient and procedural factors on hospital costs and reimbursement. A comparison of surgeons' work relative value units (wRVUs) between CRS/HIPEC and a representative sample of complex surgical oncology procedures was made to assess the physicians' compensation rate. Univariable and multivariable backward logistic regression was used to analyze the association between perioperative variables and high direct cost (HDCs). RESULTS: The median direct cost per CRS/HIPEC procedure was US $44,770. The median hospital reimbursement was US $43,066, while professional reimbursement was US $8608, resulting in a positive contribution margin of US $7493/procedure. However, the contribution margin significantly varied with the payer mix. Privately insured patients had a positive median contribution margin of US $23,033, whereas Medicare-insured patients had a negative contribution margin of US $13,034. Length of stay (LOS) had the most significant association with HDC, and major complications had the most significant association with LOS. Finally, CRS/HIPEC procedures generated a median of 13 wRVU/h, which is significantly lower than the wRVU/h generated by open pancreatoduodenectomies, open gastrectomies, and hepatectomies. However, higher operation complexity and multiple visceral resections help compensate for the relatively low wRVU/h. CONCLUSIONS: CRS/HIPEC is an expensive operation, and prolonged LOS has the most significant impact on the total cost of the procedure. High-quality care is essential to improve patient outcomes and maintain the economic sustainability of the procedure.

Kondo Effect of Co-Porphyrin: Remarkable Sensitivity to Adsorption Sites and Orientations.

We investigated the Kondo effect of cobalt(II)-5-15-bis(4'-bromophenyl)-10,20-bis(4'-iodophenyl)porphyrin (CoTPPBr2I2) molecules on Au(111) with low-temperature scanning tunneling microscopy under ultrahigh vacuum conditions. The molecules exhibit four adsorption configurations at the top and bridge sites of the surface with different molecular orientations. The Kondo resonance shows extraordinary sensitivity to the adsorption configuration. By switching the molecule between different configurations, the Kondo temperature is varied over a wide range from ≈8 up to ≈250 K. Density functional theory calculations reveal that changes of the adsorption configuration lead to distinct variations of the hybridization between the molecule and the surface. Furthermore, we show that surface reconstruction plays a significant role for the molecular Kondo effect.

7-Year (2015-21) longitudinal surveillance of lefamulin in vitro activity against bacterial pathogens collected worldwide from patients with respiratory tract infections including pneumonia and characterization of resistance mechanisms.

OBJECTIVES: Lefamulin (Xenleta™), a pleuromutilin antibiotic, was approved for the oral and IV treatment of community-acquired bacterial pneumonia (CABP) in adults in 2019/2020. This study evaluated the in vitro activity of lefamulin and comparators against 19 584 unique bacterial isolates collected from patients with community-acquired respiratory tract infections and hospitalized patients with pneumonia within the global SENTRY Antimicrobial Surveillance Program during 2015-21. METHODS: Isolates were susceptibility tested by the CLSI broth microdilution method, and resistance mechanisms were investigated in isolates with elevated lefamulin MICs. RESULTS: Lefamulin exhibited potent antibacterial activity against the most common and typical CABP pathogens tested, including Streptococcus pneumoniae [MIC50/90, 0.06/0.25 mg/L; 99.9% susceptible (S)], Staphylococcus aureus (MIC50/90, 0.06/0.12 mg/L; 99.6% S), Haemophilus influenzae (MIC50/90, 0.5/2 mg/L; 99.1% S) and Moraxella catarrhalis (MIC50/90, 0.06/0.12 mg/L; 100.0% S). Potent activity was also observed against the less common pneumonia pathogens: ß-haemolytic (MIC50/90 of 0.03/0.06 mg/L) and viridans group Streptococcus spp. (MIC50/90 of 0.06/0.25 mg/L) and Haemophilus parainfluenzae (MIC50/90 of 1/4 mg/L). Lefamulin's activity was not adversely affected by resistance to macrolides, penicillin, tetracyclines, fluoroquinolones and other resistance phenotypes. Non-susceptibility/resistance to lefamulin was rare and primarily determined by ribosomal protection through vga(A) variants in S. aureus, overexpression of AcrAB-TolC efflux pump in H. influenzae or modifications in L3, L4 and 23SrRNA in Streptococcus spp. CONCLUSIONS: Based on the coverage of the most important CABP pathogens and lacking cross-resistance, lefamulin may represent a valuable empirical treatment option for ambulatory and hospitalized patients with CABP, particularly in settings with high prevalence of resistance.