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Osteomyelitis is an inflammation of bone tissue usually caused by pyogenic bacteria. The most recurrent clinical approach consists of bone debridement followed by parenteral administration of antibiotics. However, systemic antibiotic treatment has limitations regarding absorption rate and bioavailability over time. The main challenge of osteomyelitis treatment consists of coupling the persistent infection treatment with the regeneration of the bone debrided. In this work, we developed an injectable drug delivery system based on poloxamer 407 hydrogel containing undoped Mg, Zn-doped tricalcium phosphate (β-TCP), and teicoplanin, a broad-spectrum antibiotic. We evaluated how the addition of teicoplanin and β-TCP affected the micellization, gelation, particle size, and surface charge of the hydrogel. Later, we studied the hydrogel degradation and drug delivery kinetics. Finally, the bactericidal, biocompatibility, and osteogenic properties were evaluated through in vitro studies and confirmed by in vivo Wistar rat models. Teicoplanin was found to be encapsulated in the corona portions of the hydrogel micelles, yielding a bigger hydrodynamics radius. The encapsulated teicoplanin showed a sustained release over the evaluated period, enough to trigger antibacterial properties against Gram-positive bacteria. Besides, the formulations were biocompatible and showed bone healing ability and osteogenic properties. Finally, in vivo studies confirmed that the proposed locally injected formulations yielded osteomyelitis treatment with superior outcomes than parenteral administration while promoting bone regeneration. In conclusion, the presented formulations are promising drug delivery systems for osteomyelitis treatment and deserve further technological improvements., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: The possible use of dalbavancin as a catheter lock solution was previously demonstrated by our study group. However, it was needed to assess whether heparin could affect dalbavancin bioactivity during freezing storage., Methods: We tested the bioactivity of a dalbavancin+heparin (DH) vs. dalbavancin (D) against Staphylococcal biofilms comparing DH median value of cfu counts and metabolic activity with that obtained for D before and during storage under freezing up to 6 months., Results: Despite there was a slight decrease in the median percentage reduction of metabolic activity at month 3 in Staphylococcus epidermidis between DH and D (97.6 vs. 100, p=0.037), considering the clinical criteria, no significant reduction in any of the variables tested was observed at the end of the experiment between D and DH solutions., Conclusion: The addition of heparin to a dalbavancin lock solution did not affect its bioactivity against staphylococcal biofilms irrespective of its preservation time under freezing., (Copyright © 2024 Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. Published by Elsevier España, S.L.U. All rights reserved.)

Background: The increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) strains resistant to non-beta-lactam antimicrobials poses a significant challenge in treating severe MRSA bloodstream infections. This study explores resistance development and mechanisms in MRSA isolates, especially after the first dalbavancin-resistant MRSA strain in our hospital in 2016., Methods: This study investigated 55 MRSA bloodstream isolates (02/2015-02/2021) from the University Hospital of the Medical University of Vienna, Austria. The MICs of dalbavancin, linezolid, and daptomycin were assessed. Two isolates (16-33 and 19-362) resistant to dalbavancin were analyzed via whole-genome sequencing, with morphology evaluated using transmission electron microscopy (TEM)., Results: S.aureus BSI strain 19-362 had two novel missense mutations (p.I515M and p.A606D) in the pbp2 gene. Isolate 16-33 had a 534 bp deletion in the DHH domain of GdpP and a SNV in pbp2 (p.G146R). Both strains had mutations in the rpoB gene, but at different positions. TEM revealed significantly thicker cell walls in 16-33 (p < 0.05) compared to 19-362 and dalbavancin-susceptible strains. None of the MRSA isolates showed resistance to linezolid or daptomycin., Conclusion: In light of increasing vancomycin resistance reports, continuous surveillance is essential to comprehend the molecular mechanisms of resistance in alternative MRSA treatment options. In this work, two novel missense mutations (p.I515M and p.A606D) in the pbp2 gene were newly identified as possible causes of dalbavancin resistance., (© 2024. The Author(s).)

Background and Objective: Dalbavancin is increasingly used for the long-term treatment of chronic osteoarticular infections. A population pharmacokinetic/pharmacodynamic (PK/PD) analysis for assessing the relationship between dalbavancin exposure and C-reactive protein (C-RP) over time was conducted., Methods: Non-linear mixed-effect modeling was fitted to dalbavancin and C-RP concentrations. Monte Carlo simulations assessed the weekly percentage of C-RP reduction associated with different dosing regimens, starting from baseline to < 1 mg/dL., Results: A total of 45 patients were retrospectively included in the analysis. The PK of dalbavancin was described by a two-compartment model, and the PD of C-RP was described by an indirect turnover maximum inhibition model. The total dalbavancin concentration model estimate producing 50% of maximum C-RP production inhibition (IC 50 ) was 0.70 mg/L. Monte Carlo simulations showed that in patients with staphylococcal osteoarticular infections targeting total dalbavancin concentrations at > 14.5 mg/L at any time point may achieve C-RP production inhibition over time in > 95% of patients. Based on this, the findings showed that a cumulative dose of 3000 mg administered in the first 3 weeks may lead to a > 90% C-RP decrease versus baseline in approximately 5-6 weeks. In patients needing treatment prolongation, an additional 1500 mg dose after this period may maintain C-RP concentrations < 1 mg/dL for other 3 weeks., Conclusions: A decrease in C-RP is related to dalbavancin exposure in osteoarticular infections. Targeting dalbavancin plasma concentrations above the efficacy threshold may be associated with effective treatment., (© 2024. The Author(s).)

Purpose: The Centers for Disease Control and Prevention has classified methicillin-resistant S aureus (MRSA) as a serious public health threat. The escalating minimum inhibitory concentration (MIC) of standard anti-methicillin-resistant S aureus (MRSA) drugs within the susceptible range, known as "MIC creep," jeopardizes their effectiveness against MRSA infections, posing additional challenges in managing MRSA infections. This cross-sectional study was conducted in a tertiary care hospital in Central India to assess the susceptibility trends of clinical MRSA isolates against commonly used anti-MRSA drugs and to observe MIC creep, if any, over three years (2020-2022)., Methods: The study included 158 non-repetitive clinical MRSA isolates. The MICs of vancomycin, teicoplanin, and linezolid were determined in MRSA strains using agar dilution, while the MIC of daptomycin was performed by broth microdilution. MIC creep was assessed by calculating MIC50, MIC90, Modal MIC, G-mean MIC, and susceptible and resistant percentages for the fiscal years 2020, 2021, and 2022., Results: Of the 158 MRSA isolates, none were resistant to vancomycin, teicoplanin, and daptomycin, but two showed resistance to linezolid (LRSA). However, fifteen isolates showed intermediate resistance to vancomycin (VISA), and five showed intermediate resistance to teicoplanin (TISA). MIC of these anti-MRSA drugs increased in 2021 and 2022 compared to 2020. G-mean MIC for vancomycin, teicoplanin, and linezolid in MRSA strains increased significantly over the study period, while daptomycin MIC remained relatively stable, with a slight increase in 2021 and 2022. There was a high resistance rate for clindamycin, doxycycline, and chloramphenicol among VISA, TISA, and LRSA isolates compared to MRSA., Conclusions: During the three years of the study, "MIC creep" was observed in vancomycin, teicoplanin, and linezolid and, to some extent, for daptomycin in MRSA strains. The recovery of VISA, TISA, and linezolid-resistant MRSAs is worrisome, suggesting possible MRSA treatment failure and being a forerunner of resistant strains., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Indian Association of Medical Microbiologists. Published by Elsevier B.V. All rights reserved.)

Developing hybrid hydrogel dressings with anti-inflammatory, antioxidant, angiogenetic, and antibiofilm activities with higher bone tissue penetrability to accelerate diabetic wound healing and prevent diabetic foot osteomyelitis (DFO) is highly desirable in managing diabetic wounds. Herein, the glycopeptide teicoplanin is used for the first time as a green reductant to chemically reduce graphene oxide (GO). The resulting teicoplanin-decorated reduced graphene oxide (rGO) is incorporated into a mixture of silk proteins (SP) and crosslinked with genipin to yield a physicochemically crosslinked rGO-SP hybrid hydrogel. This hybrid hydrogel exhibits high porosity, self-healing, shear-induced thinning, increased cell proliferation and migration, and mechanical properties suitable for tissue engineering. Moreover, the hybrid hydrogel eradicates bacterial biofilms with a high penetrability index in agar and hydroxyapatite disks covered with biofilms, mimicking bone tissue. In vivo, the hybrid hydrogel accelerates the healing of noninfected wounds in a diabetic rat and infected wounds in a diabetic mouse by upregulating anti-inflammatory cytokines and downregulating matrix metalloproteinase-9, promoting M2 macrophage polarization and angiogenesis. The implantation of hybrid hydrogel into the infected site of mouse tibia improves bone regeneration. Hence, the rGO-SP hybrid hydrogel can be a promising wound dressing for treating infectious diabetic wounds, providing a further advantage in preventing DFO., (© 2024 Wiley‐VCH GmbH.)

Antibiotic resistance and tolerance remain a major problem for the treatment of staphylococcal infections. Identifying genes that influence antibiotic susceptibility could open the door to novel antimicrobial strategies, including targets for new synergistic drug combinations. Here, we developed a genome-wide CRISPR interference library for Staphylococcus aureus , demonstrated its use by quantifying gene fitness in different strains through CRISPRi-seq, and used it to identify genes that modulate susceptibility to the lipoglycopeptide dalbavancin. By exposing the library to sublethal concentrations of dalbavancin using both CRISPRi-seq and direct selection methods, we not only found genes previously reported to be involved in antibiotic susceptibility but also identified genes thus far unknown to affect antibiotic tolerance. Importantly, some of these genes could not have been detected by more conventional transposon-based knockout approaches because they are essential for growth, stressing the complementary value of CRISPRi-based methods. Notably, knockdown of a gene encoding the uncharacterized protein KapB specifically sensitizes the cells to dalbavancin, but not to other antibiotics of the same class, whereas knockdown of the Shikimate pathway showed the opposite effect. The results presented here demonstrate the promise of CRISPRi-seq screens to identify genes and pathways involved in antibiotic susceptibility and pave the way to explore alternative antimicrobial treatments through these insights.IMPORTANCEAntibiotic resistance is a challenge for treating staphylococcal infections. Identifying genes that affect how antibiotics work could help create new treatments. In our study, we made a CRISPR interference library for Staphylococcus aureus and used this to find which genes are critical for growth and also mapped genes that are important for antibiotic sensitivity, focusing on the lipoglycopeptide antibiotic dalbavancin. With this method, we identified genes that altered the sensitivity to dalbavancin upon knockdown, including genes involved in different cellular functions. CRISPRi-seq offers a means to uncover untapped antibiotic targets, including those that conventional screens would disregard due to their essentiality. This paves the way for the discovery of new ways to fight infections., Competing Interests: The authors declare no conflict of interest.

Background & objectives The global prevalence of vancomycin-resistant Staphylococcus aureus (VRSA) has increased two fold since 2010, accounting for 2.4 per cent of S. aureus infections. The emerging hVISA isolates and their increasing trends pose a serious therapeutic challenge. The present study investigated in vitro vancomycin and teicoplanin minimum inhibitory concentration (MIC) creep in S. aureus and assessed their revertants. Methods A total of 845 isolates were collected for this study, and 246 were confirmed as S. aureus. Molecular characterization of vancomycin resistance was carried out by PCR assay targeting genes types viz: vanA, vanB, vanC, vanC2/C3, vanD, vanE, and vanG. MIC was determined for vancomycin and teicoplanin by agar dilution method. MIC creep and revertant analysis were done by broth dilution method in the presence and absence of antibiotics. Results PCR assay confirmed 12 isolates were harboured vanA, followed by vanD (n=8) and vanB (n=7). The study showed 69 isolates were screened positive for glycopeptide non-susceptibility. While analyzing vancomycin MIC creep, four isolates showed a significant increase in MIC, whereas no creep phenomenon was observed for the rest. In the case of teicoplanin, seven isolates showed the MIC creep phenomenon. Revertant analysis of all the isolates that showed MIC creep phenomenon for vancomycin and teicoplanin reverted to their original MIC when the antibiotic pressure was withdrawn. Interpretation & conclusions In the present study setting, glycopeptide non-susceptibility was found in eight per cent of the isolates, and the present study found the occurrence of multiple van genes from isolates calculated from a single study center will impose a serious challenge in infection control and antibiotic policy. This study also underscores that heterogenic resistant isolates, upon exposure to vancomycin and teicoplanin at a minimum level, exhibited an increase in MIC, which will impact individuals receiving glycopeptide therapy.

Objectives: This study aims to evaluate two commercial broth microdilution (BMD) systems, E1-185-100 (Merlin) and FDANDPF (ThermoFisher), for dalbavancin susceptibility testing in comparison with reference BMD assay., Methods: Study collection was composed of 200 non-replicate multidrug-resistant Gram-positive cocci of clinical origin, including 180 methicillin-resistant Staphylococcus aureus, 10 vancomycin-resistant enterococci, seven linezolid-resistant Staphylococcus epidermidis, and three methicillin-resistant coagulase-negative staphylococci. S. aureus ATCC 29213 and Enterococcus faecalis ATCC 29212 reference strains were also included as controls. Testing was performed according to the ISO 20776-1 standard, starting from the same bacterial inoculum, and results were compared according to the ISO 20776-2 standard., Results: Reference BMD showed that 92.6% (187/202) of the strains were susceptible to dalbavancin, whereas few staphylococci and all VanA-producing enterococci showed a resistant phenotype. In comparison with the reference method, Category Agreement and Essential Agreement were 98% (198/202; 95% CI, 95.4-99.3%) and 98% (198/202; 95% CI, 95.4-99.3%) for both Merlin and ThermoFisher panels. A few false susceptibilities were observed, for both commercial systems, with dalbavancin-resistant staphylococci. BIAS values of 11% and 3% were calculated for the Merlin and ThermoFisher systems, respectively., Discussion: This study, reporting the first evaluation of the two commercially available BMD assays for dalbavancin susceptibility testing, revealed an overall good correlation with reference BMD, although with some underestimation tendency of MIC values by both commercial systems. Further studies involving a higher number of resistant isolates will be necessary to better evaluate this issue., (Copyright © 2024 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

The aim of this study was to investigate the detection of teicoplanin and fosfomycin antibiotic susceptibility of methicillin-resistant Staphylococcus aureus (MRSA) strains by different methods and to evaluate the antibacterial synergistic effect of teicoplanin-fosfomycin combination by using checkerboard assay and time kill curve assay. Forty-five MRSA strains isolated from clinical samples in routine medical microbiology laboratory of Göztepe Prof. Dr. Süleyman Yalçın City Hospital were included in the study. In the first stage of the combination study, minimum inhibitory concentrations (MIC) were investigated by broth microdilution for teicoplanin and by both broth microdilution and agar dilution methods for fosfomycin. The combination of teicoplanin and fosfomycin was tested by the checkerboard method in 45 MRSA strains and combination effect was determined according to fractional inhibitory concentration index (ΣFIC) calculation. The synergistic effect and bactericidal activity of antibiotic combination were studied against a randomly selected strain from the strains used in the study by using time-kill method for 24 hours. As a result of teicoplanin and fosfomycin antibiotic susceptibility studies, all isolates were found to be susceptible to both antibiotics according to the susceptibility breakpoints determined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST). A synergistic effect was found in 22 (49%), additive effect in 22 (49%) and indifferent effect in one (2%) of the 45 strains studied with the checkerboard method. The mean ΣFIC of 45 isolates was found to be 0.5. In the combination study of the antibiotics of the isolate that was studied with time-kill method, synergism was detected for 1/8 MIC concentrations at 12th hour and 24th hour and synergism at 1/4 MIC concentration at sixth hour, 12th hour and 24th hour. In the combination study of 1/4 MIC concentrations of antibiotics, bactericidal effect was detected at sixth hour and this effect was observed to disappear at 12th and 24th hours. High rate of synergistic antibacterial effect of teicoplanin-fosfomycin combination on MRSA isolates was demonstrated as a result of in vitro tests. Such studies conducted on antibiotic-resistant bacterial infections will provide clinicians different treatment options and will contribute to increasing survival. As a result of this study, provided that it is supported by future clinical studies, it can be stated that the teicoplanin-fosfomycin combination may be an effective treatment option in community and hospital-acquired infections caused by MRSA.

The use of glycopeptide medications may decline in line with the annual decline in methicillin-resistant Staphylococcus aureus (MRSA) detection rates in China. The rate of heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA)detection may be impacted by this. However, there is currently a dearth of information on the incidence of hVISA in China. This study aims to analyze the recent epidemiology and molecular characteristics of hVISA strains in Beijing, China. A total of 175 non-duplicate MRSA strains from various infection sites were collected from a medical center between January 2018 and May 2023 and underwent molecular typing and susceptibility testing (Vitek2). Vancomycin and teicoplanin MICs were also evaluated by standard broth microdilution method and agar dilution method, respectively. Isolates growing on screening agar (BHIV4 and BHIT5, brain heart infusion agar containing 4 μg/ml vancomycin and 5 μg/ml teicoplanin, respectively) were characterized further by analysis of macro-Etest (MET) and population analysis profiling with area under the curve (PAP-AUC). The proportion of hVISA among MRSA isolates was 8.6 %. BHIT5 could select all hVISA strains while BHIV4 and MET only selected two hVISA strains. Compared with vancomycin- susceptible Staphylococcus aureus (VSSA), hVISA isolates were less susceptible to erythromycin and clindamycin. In addition, hVISA frequency was MIC-independent despite using different detection methods. In total, 11 types of STs, 28 types of spa typing, four types of SCCmec typing, and two types of agr typing were identified and the predominant type in both MRSA and hVISA isolates was ST239-t030-SCCmecIII-agr I. The analysis of biofilm formation, growth, and virulence genes in hVISA strains revealed sparse information. The dataset presented in this study provided the prevalence and molecular characteristics of hVISA in hospital settings and the combination of BHIT5 and PAP-AUC may identify hVISA efficiently. The result of genotyping suggested the genotype of hVISA was mainly consistent with that of local MRSA. Additional studies on the characteristics of hVISA strains were necessary., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Therapeutic options for staphylococcus infections have been raised due to the emergence of VISA and VRSA. Six isolates of Staphylococcus aureus of clinical origin which were previously confirmed to carry vanG were selected for this study. Antimicrobial susceptibility was performed by disc diffusion method. Transcriptional expression of vanG and vanS G showed down regulation against vancomycin and teicoplanin but expression was increased with increasing concentration of antibiotics. vanU G , vanR G showed up regulation against glycopeptide exposure. The present study underscored that expression of vanG and its regulatory gene operons are dependent on concentration of vancomycin and teicoplanin exposure in S.aureus., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Indian Association of Medical Microbiologists. Published by Elsevier B.V. All rights reserved.)

Dalbavancin is increasingly being used for long-term treatment of subacute and chronic staphylococcal infections. In this study, a new Bayesian model was implemented and validated using MwPharm software for accurately forecasting the duration of pharmacodynamic target attainment above the efficacy thresholds of 4.02 mg/L or 8.04 mg/L against staphylococci. Forecasting accuracy improved substantially with the a posteriori approach compared with the a priori approach, particularly when two measured concentrations were used. This strategy may help clinicians to estimate the duration of optimal exposure with dalbavancin in the context of long-term treatment., (Copyright © 2023 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Objectives: Teicoplanin is a potential antimicrobial candidate for Clostridioides difficile infection (CDI) treatment. However, the therapeutic potential of teicoplanin against severe CDI has not been clinically proven. In the present study, we investigated the efficacy of oral teicoplanin administration against severe CDI and the recurrence of severe CDI after teicoplanin treatment in a mouse model., Methods: A lethal CDI mouse model was established by colonizing the mice with C. difficile ATCC® 43255; they were orally administered teicoplanin (128 mg/kg/d) or vancomycin (160 mg/kg/d) for 10 d, 24 h after C. difficile spore challenge, and physiological and biological responses were monitored for 20 d after the initial antibiotic treatment. We also performed the in vitro time-kill assay and determined minimum inhibitory concentration (MIC), post-antibiotic effect, and toxin production with antibiotic exposure., Results: The therapeutic response (survival rates, body weight change, clinical sickness score grading, C. difficile load, and toxin titer in feces) of oral teicoplanin administration was comparable to that of oral vancomycin administration in the lethal CDI mouse model. Moreover, teicoplanin treatment suppressed the re-onset of diarrhea and re-increase in toxin titer 10 d after treatment compared with that by vancomycin treatment. In in vitro experiments, teicoplanin exhibited time-dependent antibacterial activity and possessed lower MIC and longer post-antibiotic effect than vancomycin against C. difficile. C. difficile toxin production was numerically lower with teicoplanin exposure than with vancomycin exposure., Conclusions: The results obtained from the present basic experiments could suggest that teicoplanin is a potential antibiotic for the treatment of severe CDI with recurrence-prevention activity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Antibiotics are central to modern medicine, and yet they are mainly the products of intra and inter-kingdom evolutionary warfare. To understand how nature evolves antibiotics around a common mechanism of action, we investigated the origins of an extremely valuable class of compounds, lipid II targeting glycopeptide antibiotics (GPAs, exemplified by teicoplanin and vancomycin), which are used as last resort for the treatment of antibiotic resistant bacterial infections. Using a molecule-centred approach and computational techniques, we first predicted the nonribosomal peptide synthetase assembly line of paleomycin, the ancestral parent of lipid II targeting GPAs. Subsequently, we employed synthetic biology techniques to produce the predicted peptide and validated its antibiotic activity. We revealed the structure of paleomycin, which enabled us to address how nature morphs a peptide antibiotic scaffold through evolution. In doing so, we obtained temporal snapshots of key selection domains in nonribosomal peptide synthesis during the biosynthetic journey from ancestral, teicoplanin-like GPAs to modern GPAs such as vancomycin. Our study demonstrates the synergy of computational techniques and synthetic biology approaches enabling us to journey back in time, trace the temporal evolution of antibiotics, and revive these ancestral molecules. It also reveals the optimisation strategies nature has applied to evolve modern GPAs, laying the foundation for future efforts to engineer this important class of antimicrobial agents., (© 2023. The Author(s).)

Introduction: The aim was to investigate the in vitro activity of ceftobiprole and dalbavancin against a collection of coagulase-negative staphylococci (CoNS) isolates with reduced susceptibility to daptomycin or resistant to linezolid and/or glycopeptides., Methods: A total of 228 CoNS were tested using the Vitek-2 AST-626 cards (bioMérieux) and MIC of daptomycin, linezolid, vancomycin and teicoplanin were confirmed by Etest Strips (bioMérieux). Susceptibility testing for ceftobiprole and dalbavancin were performed by CLSI broth microdilution methodology. Results were interpreted according to 2021 EUCAST clinical breakpoints., Results: Ceftobiprole and dalbavancin were active against 96.0% and 93.0% of CoNS, respectively, MIC 90 were 2 and 0.125mg/L. MICs of ceptobiprole were higher against S. hominis and S. haemolyticus (MIC 90 4mg/L). Dalbavancin exhibited higher MICs against S. haemolyticus and CoNS with reduced susceptibility to daptomycin and resistant to teicoplanin., Conclusion: Ceftobiprole and dalbavancin demonstrated a high in vitro activity against our collection of CoNS isolates., (Copyright © 2022 Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. Published by Elsevier España, S.L.U. All rights reserved.)

Purpose: Vancomycin and linezolid are first-line drugs used for the prophylaxis and treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. Vancomycin is well known as the best alternative drug when linezolid-induced thrombocytopenia occurs. However, several cases with vancomycin-induced thrombocytopenia, especially with bleeding complications, have been reported recently, which has attracted attention. The objective of this study is to assess the potential relevance between vancomycin and bleeding complications in thrombocytopenia., Methods: This is a real-world pharmacovigilance study conducted in October 2022 using the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. We performed a disproportional analysis to assess the risk of bleeding complications in vancomycin-induced thrombocytopenia by calculating reporting odds ratios (RORs) and information components (ICs), with a weak signal defined as a lower limit of the IC 95% CI of 0 to 1.5, a middle signal defined as a lower limit of the IC 95% CI of 1.5 to 3.0, and a strong signal defined as a lower limit of the IC 95% CI of >3.0., Findings: There were 21,854 cases in the FAERS database that listed vancomycin as a suspected drug from quarter 1 of 2004 to quarter 2 of 2022. There were 800 cases of vancomycin-induced thrombocytopenia and 125 cases of bleeding complications in vancomycin-induced thrombocytopenia. Teicoplanin, tigecycline, and vancomycin (3 middle signals) were sequentially less associated with thrombocytopenia than linezolid (strong signal). However, bleeding complications in thrombocytopenia were significant associated with vancomycin (ROR = 9.641; 95% CI, 8.105-11.468; IC = 3.184; 95% CI, 2.929-3.440 [middle signal]), followed by linezolid (ROR = 9.350; 95% CI, 7.318-11.947; IC = 3.106; 95% CI, 2.745-3.466 [middle signal]), teicoplanin (ROR = 6.399; 95% CI, 2.869-14.272; IC = 2.059; 95% CI, 0.881-3.283 [weak signal]), and daptomycin (ROR = 2.784; 95% CI, 1.496-5.180; IC = 1.287; 95% CI, 0.374-2.201 [weak signal]). Tigecycline and daptomycin were the least likely anti-MRSA drug to cause thrombocytopenia (middle signal and weak signal, respectively) and bleeding complications in thrombocytopenia (no signal and weak signal, respectively). Middle signals of bleeding complication in vancomycin-induced thrombocytopenia were found in all group except those <45 to ≥80 years of age (weak signal)., Implications: Bleeding complications in thrombocytopenia were significantly associated with vancomycin use, and the risk was highest among all the anti-MRSA drugs. Physicians should be aware of this possible serious adverse reaction., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Glycopeptide antibiotics (vancomycin and teicoplanin) are usually used for the treatment of Staphylococcus epidermidis infections owing to their increased oxacillin resistance. However, S. epidermidis strains with decreased susceptibility to teicoplanin have become increasingly incident in recent years. We aimed to identify the characteristics of teicoplanin-non-susceptible (Teico-NS) S. epidermidis isolated at our hospital and analyze its relationship with teicoplanin usage. We retrospectively evaluated 328 S. epidermidis strains isolated from clinical isolates between January 2016 and December 2021. All strains were susceptible to vancomycin (minimal inhibitory concentration (MIC) ≤ 4 mg/L). The annual incidence for S. epidermidis strains with an elevated teicoplanin MIC of 8 mg/L ranged from 22.2 to 28.9%. In addition, in 2021, the number of S. epidermidis strains with teicoplanin MIC ≥ 16 mg/L rapidly increased (n = 13, 32.5%). Furthermore, teicoplanin use increased annually until 2019; however, in 2020, it decreased abruptly due to the COVID 19 pandemic. Thus, we could not confirm the existence of a clear correlation between teicoplanin usage and increased incidence of S. epidermidis with reduced teicoplanin-susceptibility. We showed the increased incidence of Teico-NS S. epidermidis in recent years. Further studies are needed to identify the mechanisms and risk factors for teicoplanin-resistance in S. epidermidis., (© 2023. Springer Nature Limited.)

Staphylococcus aureus is a global pathogen and is responsible for causing severe life-threatening infections. The current study was designed to investigate transcriptional expression of different core, regulatory, and accessory genes within vanB operon under differential exposure of vancomycin and teicoplanin. Four isolates selected for the study, were confirmed to harbour vanB gene in which three isolates showed MIC breakpoint above 16 µg/ml and one isolate above 8 µg/ml against vancomycin while teicoplanin showed higher MIC breakpoint as compared to vancomycin. Antibiotic susceptibility results showed that these isolates were susceptible towards imipenem and linezolid. Transcriptional expressional analysis of the core gene of vanB operon showed that expression of vanB is increased under vancomycin stress but is inversely proportional to increase in the concentration of the vancomycin while under teicoplanin stress the expression of vanB showed no significant pattern. Similar expressional pattern was found for vanH gene for both the glycopeptides. In case of vanX, expression was significantly increased at 1 µg/ml exposure of vancomycin, however, no pattern could be observed in case of teicoplanin stress. In case of regulatory gene, vanR, significant increase in expression was observed under vancomycin and teicoplanin stress of 1 µg/ml, however vanS, showed significant increase in the expression under 1 µg/ml of vancomycin. The accessory gene, vanY showed marginal increase in expression under both the antibiotic, while in case of vanW, the expressional pattern was found to be inversely proportional to the increasing antibiotic concentration., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: This study aimed to determine the inhibitory and bactericidal effects of teicoplanin (TEC) on TEC-susceptible Staphylococcus haemolyticus isolated from a patient with cancer in whom infection persisted despite TEC therapy. We also focused on the biofilm-forming ability of the isolate in vitro., Methods: S. haemolyticus clinical isolate (strain 1369A) and its control strain, ATCC 29970 were cultured in Luria-Bertani (LB) broth with TEC. The inhibitory and bactericidal effects of TEC on planktonic, adherent, biofilm-dispersed, and biofilm-embedded cells of these strains were analyzed by using a biofilm formation/viability assay kit. The expression of biofilm-related genes was measured using quantitative real-time polymerase chain reaction (qRT-PCR). Biofilm formation was determined by using scanning electron microscopy (SEM)., Results: The clinical isolate of S. haemolyticus had enhanced ability to bacterial growth, adherence, aggregation, and biofilm formation, thus the inhibitory and bactericidal effects of TEC on planktonic, adherent, biofilm-dispersed, and biofilm-embedded cells of the isolate were attenuated. Additionally, TEC induced cell aggregation, biofilm formation, and some biofilm-related gene expression of the isolate., Conclusion: The clinical isolate of S. haemolyticus is resistant to TEC treatment due to cell aggregation and biofilm formation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yoshinori Sato reports financial support was provided by JSPS KAKENHI. Yoshinori Sato reports financial support was provided by ACRO Incubation Grants of Teikyo University., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: The ability of Spanish microbiology laboratories to (a) determine antimicrobial susceptibility (AS), and (b) correctly detect the vancomycin resistance (VR) phenotype in vancomycin-resistant Enterococcus spp. (VRE) was evaluated., Methods: Three VRE isolates representing the VanA (E. faecium), VanB (E. faecium) and VanC (E. gallinarum) VR phenotypes were sent to 52 laboratories, which were asked for: (a) AS method used; (b) MICs of ampicillin, imipenem, vancomycin, teicoplanin, linezolid, daptomycin, ciprofloxacin, levofloxacin and quinupristin-dalfopristin, and high-level resistance to gentamicin and streptomycin; (c) VR phenotype., Results: (a) The most frequently used system was MicroScan; (b) according to the system, the highest percentage of discrepant MICs was found with gradient strips (21.3%). By antimicrobial, the highest rates of discrepant MICs ranged 16.7% (imipenem) to 0.7% (linezolid). No discrepant MICs were obtained with daptomycin or levofloxacin. Mayor errors (MEs) occurred with linezolid (1.1%/EUCAST) and ciprofloxacin (5.0%/CLSI), and very major errors (VMEs) with vancomycin (27.1%/EUCAST and 33.3%/CLSI) and teicoplanin (5.7%/EUCAST and 2.3%/CLSI). For linezolid, ciprofloxacin, and vancomycin, discrepant MICs were responsible for these errors, while for teicoplanin, errors were due to a misassignment of the clinical category. An unacceptable high percentage of VMEs was obtained using gradient strips (14.8%), especially with vancomycin, teicoplanin and daptomycin; (c) 86.4% of the centers identified VanA and VanB phenotypes correctly, and 95.0% the VanC phenotype., Conclusion: Most Spanish microbiology laboratories can reliably determine AS in VRE, but there is a significant percentage of inadequate interpretations (warning of false susceptibility) for teicoplanin in isolates with the VanB phenotype., (Copyright © 2021 Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. Published by Elsevier España, S.L.U. All rights reserved.)

Objectives: Gram-positive cocci is the main pathogen responsible for early infection after liver transplantation (LT), posing a huge threat to the prognosis of liver transplant recipients. This study aims to analyze the distribution and drug resistance of Gram-positive cocci, the risk factors for infections and efficacy of antibiotics within 2 months after LT, and to guide the prevention and treatment of these infections., Methods: In this study, data of pathogenic bacteria distribution, drug resistance and therapeutic efficacy were collected from 39 Gram-positive cocci infections among 256 patients who received liver transplantation from donation after citizens' death in the Third Xiangya Hospital of Central South University from January 2019 to July 2022, and risk factors for Gram-positive cocci infection were analyzed., Results: Enterococcus faecium was the dominant pathogenic bacteria (33/51, 64.7%), followed by Enterococcus faecalis (11/51, 21.6%). The most common sites of infection were abdominal cavity/biliary tract (13/256, 5.1%) and urinary tract (10/256, 3.9%). Fifty (98%) of the 51 Gram-positive cocci infections occurred within 1 month after LT. The most sensitive drugs to Gram-positive cocci were teicoplanin, tigecycline, linezolid and vancomycin. Vancomycin was not used in all patients, considering its nephrotoxicity. Vancomycin was not administered to all patients in view of its nephrotoxicity.There was no significant difference between the efficacy of daptomycin and teicoplanin in the prevention of cocci infection ( P >0.05). Univariate analysis indicated that preoperative Model for End-Stage Liver Disease (MELD) score >25 ( P =0.005), intraoperative red blood cell infusion ≥12 U ( P =0.013) and exposure to more than 2 intravenous antibiotics post-LT ( P =0.003) were related to Gram-positive cocci infections. Multivariate logistic regression analysis revealed that preoperative MELD score >25 ( OR =2.378, 95% CI 1.124 to 5.032, P =0.024) and intraoperative red blood cell transfusion ≥ 12 U ( OR =2.757, 95% CI 1.227 to 6.195, P =0.014) were independent risk factors for Gram-positive cocci infections after LT. Postoperative Gram-positive cocci infections were reduced in LT recipients exposing to more than two intravenous antibiotics post-LT ( OR =0.269, 95% CI 0.121 to 0.598, P =0.001)., Conclusions: Gram-positive cocci infections occurring early after liver transplantation were dominated by Enterococcus faecalis infections at the abdominal/biliary tract and urinary tract. Teicoplanin, tigecycline and linezolid were anti-cocci sensitive drugs. Daptomycin and teicoplanin were equally effective in preventing cocci infections due to Gram-positive cocci. Patients with high preoperative MELD score and massive intraoperative red blood cell transfusion were more likely to suffer Gram-positive cocci infection after surgery. Postoperative Gram-positive cocci infections were reduced in recipients exposing to more than two intravenous antibiotics post-LT.

Dalbavancin, a long-acting lipoglycopeptide antibiotic targeting susceptible Gram-positive bacteria, is WHO critically important antibiotic, increasingly used in critical situations such as osteoarticular infections. To ensure its effectiveness and its safety, the therapeutic drug monitoring (TDM) of dalbavancin is strongly recommended. In the absence of an available minimum inhibitory concentration (MIC), the European Committee on Antimicrobial Susceptibility Testing (EUCAST) recommends a breakpoint of 0.125 mg/L for Staphylococcus aureus, corresponding to a trough target concentration of 25 mg/L. Nowadays, the TDM is usually performed using a high-performance liquid chromatography (HPLC) method coupled with a tandem mass spectrometry. However, this expensive and specialized equipment and reagents may be difficult to acquire for non-specialized laboratories. The use of HPLC coupled with diode array detector (DAD) facilitates TDM with a lower cost, while preserving the reliability of the results. Our aim was to provide a sensitive and specific method, relying on HPLC-DAD for extending the TDM of dalbavancin beyond non-specialized labs, therefore maximizing its efficiency and Benefit/risk ratio. Our method complied with the European Medicines Agency guidelines of bioanalytical validation. Irrespective of the concentrations of dalbavancin, the coefficient of variation < 10% confirmed the reliability of this analytical method, with a calibration curve ranging from 5 to 100 mg/L. No interferences nor carryover was observed. Our HPLC-DAD method, combined with a simple extraction, provides a widely usable, inexpensive and easy-to-implement new asset for the TDM of Dalbavancin., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The rapid emergence of highly transmissible SARS-CoV-2 variants poses serious threat to the efficacy of vaccines and neutralizing antibodies. Thus, there is an urgent need to develop new and effective inhibitors against SARS-CoV-2 and future outbreaks. Here, we have identified a series of glycopeptide antibiotics teicoplanin derivatives that bind to the SARS-CoV-2 spike (S) protein, interrupt its interaction with ACE2 receptor and selectively inhibit viral entry mediated by S protein. Computation modeling predicts that these compounds interact with the residues in the receptor binding domain. More importantly, these teicoplanin derivatives inhibit the entry of both pseudotyped SARS-CoV-2 Delta and Omicron variants. Our study demonstrates the feasibility of developing small molecule entry inhibitors by targeting the interaction of viral S protein and ACE2. Together, considering the proven safety and pharmacokinetics of teicoplanin as a glycopeptide antibiotic, the teicoplanin derivatives hold great promise of being repurposed as pan-SARS-CoV-2 inhibitors., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Masson SAS.)

Polymorphonuclear leukocytes (PMNs) are the most important cell type involved in the early nonspecific host response to bacterial pathogens. Staphylococcus aureus has evolved mechanisms to evade immune responses that contribute to its persistence in PMNs, and acquired resistance to several antimicrobials. Additionally, methicillin-resistant S. aureus (MRSA) is one of the most common causes of acute bacterial skin and skin-structure infections (ABSSSIs). Dalbavancin (DBV), a lipoglycopeptide, is indicated for the treatment of ABSSSIs, and has a broad spectrum of action against most microorganisms. Here, we sought to determine the effect of DBV on the neutrophil killing of MRSA and its potential immunomodulating activity. Our results revealed that DBV boosts MRSA killing by acting on both bacteria and PMNs. DBV pre-treatment of PMNs did not change the respiratory burst or degranulation, while an increased trend in neutrophil extracellular traps-associated elastase and in the production of TNFα and CXCL8 was revealed. In parallel, DBV caused a delay in the apoptosis of MRSA-infected neutrophils. In conclusion, we demonstrated a cooperative effect between the antimicrobial properties of PMNs and DBV, thus owing to their immunomodulatory activity. In the choice of the treatment management of serious S. aureus infections, DBV should be considered as an outstanding option since it reinforces PMNs pathogen clearance capability by exerting its effect directly, not only on MRSA but also on neutrophils.

Tunneled central venous catheter (TCVC) related infection remains a challenge in the care of hemodialysis patients. We aimed to determine the best antimicrobial lock therapy (ALT) to eradicate coagulase-negative staphylococci (CoNS) biofilms. We studied the colonization status of the catheter every 30 days by quantitative blood cultures (QBC) drawn through all catheter lumens. Those patients with a significant culture (i.e.,100 to 1,000 CFU/mL) of a CoNS were classified as patients with a high risk of developing catheter-related bloodstream infections (CRBSI). They were assigned to receive daptomycin, vancomycin, teicoplanin lock solution, or the standard of care (SoC) (i.e., heparin lock). The primary endpoint was to compare eradication ability (i.e., negative QBC for 30 days after ending ALT) rates between different locks and the SoC. A second objective was to analyze the correlation between ALT exposure and isolation of CoNS with antimicrobial resistance. Daptomycin lock was associated with a significant higher eradication success than with the SoC: 85% versus 30% (relative risk [RR] = 14, 95% confidence interval [CI] = 2.4 - 82.7); followed by teicoplanin locks with a 83.3% success (RR = 11.7; 95% CI = 2 - 70.2). We observed CoNs isolates with a higher teicoplanin MIC in patients with repeated teicoplanin locks exposure (coefficient = 0.3; 95% CI = 0.11 - 0.47). However, teicoplanin MICs decreased in patients treated with vancomycin locks (coefficient = -0.56; 95% CI = -0.85 - -0.02). Methicillin-resistance decreased with accumulative ALT (RR = 0.82; 95% CI = 0.69 - 0.98). In this study, daptomycin locks achieve the highest eradication rate of CoNS from hemodialysis catheters in vivo .

Background: Enterococcus faecalis remains one of the most common pathogens causing infection in surgical patients. Our goal was to evaluate the antibiotic resistance of E. faecalis, causing infections in a surgical clinic, against two antibacterial drugs, ampicillin and teicoplanin. One commonly administered in the past for such infections, ampicillin, and another newer, teicoplanin, which demonstrated exceptionally good efficacy., Methods: Data from 1882 isolates were retrieved from the microbiology department database during two 5-year periods. Standard biochemical methods were employed for the identification of the isolates. The prevalence of E. faecalis among patients with clinical evidence of infection in a surgical oncology ward was assessed. Confidence interval (CI) as well as standard error (SE) were calculated. Moreover, the annual incidence of E. faecalis infections in this surgical ward was recorded. The susceptibility of E. faecalis to ampicillin and teicoplanin was studied and compared using Fisher's exact test., Results and Conclusion: Results showed that the incidence of E. faecalis infections in the surgical clinic was increasing. Ampicillin, in the later year period, was not statistically different from teicoplanin in treating E. faecalis infections. Consequently, ampicillin seems currently to be an effective antibiotic against such infections that could be used as empiric therapy., (© 2023. The Author(s).)

Introduction: Neutrophilic granulocytes represent the first line of defense against microorganisms. Granulocytes phagocytose microorganisms and specifically synthesize oxygen radicals against them, which eventually kills the invaders., Methods: Neutrophilic granulocytes were isolated from peripheral blood of healthy volunteer donors. Putative interference of new-generation antibiotics with neutrophil function was tested using a collection of granulocyte-stimulating agents and Amplex™ Red-based plate assay and flow cytometry-based respiratory burst assays. In addition, phagocytosis of E. coli, IL-8 production, bactericidal activity, and CD62L expression of granulocytes were evaluated., Results: Of note, we found that the two glycopeptide antibiotics dalbavancin and teicoplanin inhibited ROS production upon granulocyte activation via different signaling pathways in a dose-dependent manner. Dalbavancin also blocked the PMA-induced shedding of CD62L. In contrast, the oxazolidinone antibiotics tedizolid and linezolid had no effect on neutrophil function, while the combination of ceftazidime/avibactam dose dependently inhibited the fMLP/Cytochalasin B-induced granulocyte burst in a dose-dependent manner. Additionally, we showed that dalbavancin and teicoplanin as well as sulfametrole/trimethoprim and ceftazidime/avibactam inhibited baseline and PMA-induced IL-8 production by neutrophilic granulocytes. Moreover, dalbavancin impaired the bactericidal activity of neutrophilic granulocytes., Conclusion: We here identified hitherto unknown inhibitory effects of several classes of antibiotics on the effector functions of neutrophilic granulocytes., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Glycopeptide antibiotics (GPAs) are among the most clinically successful antimicrobials. GPAs inhibit cell-wall biosynthesis in Gram-positive bacteria via binding to lipid II. Natural GPAs are produced by various actinobacteria. Being themselves Gram-positives, the GPA producers evolved sophisticated mechanisms of self-resistance to avoid suicide during antibiotic production. These self-resistance genes are considered the primary source of GPA resistance genes actually spreading among pathogenic enterococci and staphylococci. The GPA-resistance mechanism in Actinoplanes teichomyceticus—the producer of the last-resort-drug teicoplanin—has been intensively studied in recent years, posing relevant questions about the role of Tei3 sensor histidine kinase. In the current work, the molecular properties of Tei3 were investigated. The setup of a GPA-responsive assay system in the model Streptomyces coelicolor allowed us to demonstrate that Tei3 functions as a non-inducible kinase, conferring high levels of GPA resistance in A. teichomyceticus. The expression of different truncated versions of tei3 in S. coelicolor indicated that both the transmembrane helices of Tei3 are crucial for proper functioning. Finally, a hybrid gene was constructed, coding for a chimera protein combining the Tei3 sensor domain with the kinase domain of VanS, with the latter being the inducible Tei3 ortholog from S. coelicolor. Surprisingly, such a chimera did not respond to teicoplanin, but indeed to the related GPA A40926. Coupling these experimental results with a further in silico analysis, a novel scenario on GPA-resistance and biosynthetic genes co-evolution in A. teichomyceticus was hereby proposed.

Gram-negative bacteria possess intrinsic resistance to glycopeptide antibiotics so these important antibacterial medications are only suitable for the treatment of Gram-positive bacterial infections. At the same time, polymyxins are peptide antibiotics, structurally related to glycopeptides, with remarkable activity against Gram-negative bacteria. With the aim of breaking the intrinsic resistance of Gram-negative bacteria against glycopeptides, a polycationic vancomycin aglycone derivative carrying an n-decanoyl side chain and five aminoethyl groups, which resembles the structure of polymyxins, was prepared. Although the compound by itself was not active against the Gram-negative bacteria tested, it synergized with teicoplanin against Escherichia coli, Pseudomonas aeruginosa and Acinetobacter baumannii, and it was able to potentiate vancomycin against these Gram-negative strains. Moreover, it proved to be active against vancomycin- and teicoplanin-resistant Gram-positive bacteria., (© 2022. The Author(s).)

The study aimed to identify colonized patients as a possible source of eventual VRE (vancomycin-resistant enterococci) infection from stool samples positive for glutamate dehydrogenase antigen, as well as for Clostridioides difficile toxins A and B. The study was carried out from 7/2020 to 9/2021. Stool samples were grown in a brain heart infusion medium with a gram-positive non-spore-forming bacteria supplement under aerobic conditions. The samples for VRE identification were grown on CHROMID ® VRE agar, and the MICs for vancomycin and teicoplanin were also estimated. The presence of the vanA/vanB genes was tested using the PCR method. The total number of 113 stool samples positive for Clostridioides difficile toxins was analyzed. Of these samples, 44 isolates with VRE characters were identified. The most prevalent isolates in our set of isolates were Enterococcus faecium (27 isolates, 62%), Enterococcus faecalis (9 isolates, 21%), Enterococcus solitarius (4 isolates, 9%), Enterococcus durans (2 isolates, 4%), 1 isolate Enterococcus sulfurous (2%), and Enterococcus raffinosus (2%). In total, 26 isolates were detected in the study in the presence of vanA genes (24 isolates E. faecium, 2 isolates E. faecalis) and 18 isolates detected in the presence of vanB genes (7 isolates E. faecalis, 4 isolates E. solitarius, 3 isolates E. faecium, 2 isolates E. durans, 1 isolate E. sulfurous, and E. raffinosus). The results of this study showed the local dominance character of the vanA gene of hospital VRE isolates that were carriers of genes associated with high resistance to vancomycin, teicoplanin, and occasionally linezolid., (© 2022. Institute of Microbiology, Academy of Sciences of the Czech Republic, v.v.i.)

Objective: To determine the frequency and antibiotic susceptibility pattern of CA-MRSA in patients with uncomplicated skin and soft tissue infections reporting to the dermatology outpatient of a tertiary health care hospital., Study Design: A descriptive study., Place and Duration of Study: Dermatology outpatient of a tertiary care hospital in Punjab province of Pakistan, from September 2020 to August 2021., Methodology: Patients of all age groups and both genders reporting during the study period with community-associated uncomplicated bacterial skin and soft tissue infections were enrolled in the study. Samples were collected from skin lesions and cultured on blood agar and MacConkey agar plates. Antimicrobial susceptibility testing using the modified Kirby Baur disc diffusion technique was performed., Results: A total of 157 patients were included in the study. Impetigo was most common infection (n=80, 51%), followed by Furunculosis (n=47, 29.9%). The frequency of MRSA isolates was 54.1% (n=85). MRSA was significantly more frequently isolated from patients with furunculous, carbuncle and cutaneous abscesses as compared to impetigo. All MRSA isolates were sensitive to linezolid, teicoplanin, and vancomycin. 97.6%, 84.7%, and 72.9% of MRSA isolates were sensitive to rifampicin, minocycline, and fusidic acid respectively. 89.4% of MRSA were sensitive to amikacin and clindamycin. 63.5% were sensitive to doxycycline and 58.8% were sensitive to co-trimoxazole. Only 20% of MRSA were sensitive to ciprofloxacin., Conclusion: The antibiotics active against CA-MRSA including rifampicin, minocycline, amikacin, and clindamycin may be used empirically in patients with furunculosis, cutaneous abscess, and carbuncles. Linezolid, teicoplanin, and vancomycin should be reserved for severe infections., Key Words: Uncomplicated skin and soft tissue infections, Community-associated Methicillin-resistant staphylococcus aureus (CA-MRSA), Antibiotic susceptibility pattern.

A patient with end-stage renal disease received 2 doses of dalbavancin for methicillin-resistant Staphylococcus aureus (MRSA) arteriovenous fistula infection and presented 5 weeks later with infective endocarditis secondary to vancomycin, daptomycin, and dalbavancin nonsusceptible MRSA. Resistance was associated with walK and scrA mutations, reduced long-chain lipid content, and reduced membrane fluidity., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Antibacterial bone biomaterial coatings appeal to orthopaedics, dentistry and veterinary medicine. Achieving the successful, stable conjugation of suitable compounds to biomaterial surfaces is a major challenge. A pragmatic starting point is to make use of existing, approved antibiotics which are known to remain functional in a stationary, immobilised state. This includes the macrocyclic glycopeptide, teicoplanin, following the discovery, in the 1990's, that it could be used as a chiral selector in chromatographic enantiomeric separations. Importantly teicoplanin works at the level of the bacterial cell wall making it a potential candidate for biomaterial functionalisations. We initially sought to functionalise titanium (Ti) with polydopamine and use this platform to capture teicoplanin, however we were unable to avoid the natural affinity of the antibiotic to the oxide surface of the metal. Whilst the interaction between teicoplanin and Ti was robust, we found that phosphate resulted in antibiotic loss. Before contemplating the covalent attachment of teicoplanin to Ti we examined whether a commercial teicoplanin stationary phase could kill staphylococci. Whilst this commercially available material could bind N-Acetyl-L-Lys-D-Ala-D-Ala it was unable to kill bacteria. We therefore strongly discourage attempts at covalently immobilising teicoplanin and/or other glycopeptide antibiotics in the pursuit of novel antibacterial bone biomaterials., (© 2022. The Author(s).)

Patients infected with SARS-CoV-2 risk co-infection with Gram-positive bacteria, which severely affects their prognosis. Antimicrobial drugs with dual antiviral and antibacterial activity would be very useful in this setting. Although glycopeptide antibiotics are well-known as strong antibacterial drugs, some of them are also active against RNA viruses like SARS-CoV-2. It has been shown that the antiviral and antibacterial efficacy can be enhanced by synthetic modifications. We here report the synthesis and biological evaluation of seven derivatives of teicoplanin bearing hydrophobic or superbasic side chain. All but one teicoplanin derivatives were effective in inhibiting SARS-CoV-2 replication in VeroE6 cells. One lipophilic and three perfluoroalkyl conjugates showed activity against SARS-CoV-2 in human Calu-3 cells and against HCoV-229E, an endemic human coronavirus, in HEL cells. Pseudovirus entry and enzyme inhibition assays established that the teicoplanin derivatives efficiently prevent the cathepsin-mediated endosomal entry of SARS-CoV-2, with some compounds inhibiting also the TMPRSS2-mediated surface entry route. The teicoplanin derivatives showed good to excellent activity against Gram-positive bacteria resistant to all approved glycopeptide antibiotics, due to their ability to dually bind to the bacterial membrane and cell-wall. To conclude, we identified three perfluoralkyl and one monoguanidine analog of teicoplanin as dual inhibitors of Gram-positive bacteria and SARS-CoV-2., (© 2022. The Author(s).)

The long-acting lipoglycopeptides (LGPs) dalbavancin and oritavancin are semisynthetic antimicrobials with broad and potent activity against Gram-positive bacterial pathogens. While they are approved by the Food and Drug Administration for acute bacterial skin and soft tissue infections, their pharmacological properties suggest a potential role of these agents for the treatment of deep-seated and severe infections, such as bloodstream and bone and joint infections. The use of these antimicrobials is particularly appealing when prolonged therapy, early discharge, and avoidance of long-term intravascular catheter access are desirable or when multidrug-resistant bacteria are suspected. This review describes the current evidence for the use of oritavancin and dalbavancin in the treatment of invasive infections, as well as the hurdles that are preventing their optimal use. Moreover, this review discusses the current knowledge gaps that need to be filled to understand the potential role of LGPs in highly needed clinical scenarios and the ongoing clinical studies that aim to address these voids in the upcoming years.

Background: Infections with multidrug-resistant Gram-negative bacteria such as Acinetobacter baumannii are major cause of morbidity and mortality. Colistin is used commonly to treat these infections. In this study, we evaluated the efficacy of different colistin combinations in a A. baumannii infection mouse model. Materials & methods: An A. baumannii mouse infection model was developed in 150 experimental animals. Treatment groups were as follows: colistin, colistin + rifampicin, colistin + trimethoprim/sulfamethoxazole, colistin + teicoplanin and a control group. The outcome was bacterial burden in the lung and liver tissues. The treatment groups were subdivided into 24-, 48- and 72-h groups. Results: Colistin and combinations reduce the A. baumannii burden significantly in lung and liver tissues compared with the control group. Compared with colistin alone colistin + rifampicin and colistin + TMP-SMX provided significantly better reduction in the bacterial burden. Conclusion: These results may suggest that rifampicin and TMP-SMX combination with colistin may have a potential role in the treatment of A. baumannii infections.

Dalbavancin is a synthetic lipoglycopeptide that exerts its antimicrobial activity through two distinct modes of action, inhibition of cell wall synthesis and an anchoring mechanism. Compared with previous glycopeptide antibiotics, dalbavancin demonstrates improved antibacterial potency against Gram-positive organisms and a long half-life of approximately 1 week, which is longer in tissues (e.g., skin, bone) than plasma. These factors facilitated the development of single-dose or once-weekly dosing regimens to treat acute bacterial skin and skin structure infections (ABSSSI). Dalbavancin exhibits dose-proportional pharmacokinetics and is highly protein bound (93%). Despite being highly protein bound, it has a steady-state volume of distribution >10 L and distributes widely into the skin, bone, peritoneal space, and epithelial lining fluid, but not cerebrospinal fluid. Dalbavancin elimination occurs via a combination of renal (approximately 45%) and non-renal clearance, with dose adjustments recommended only in patients with a creatinine clearance <30 mL/min not receiving any form of dialysis. The established pharmacokinetic/pharmacodynamic index associated with bacterial kill is free area under the concentration-time curve over the minimum inhibitory concentration (fAUC/MIC), with a goal 24-h fAUC/MIC of at least 27.1 for Staphylococcus aureus infections. Recent data suggest usefulness in the treatment of infections beyond ABSSSI, with convenient dosing and redosing strategies for complicated infections requiring extended treatment durations. Additional studies are needed to confirm these preliminary findings., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objectives: The aim of this study was to evaluate the occurrence of glycopeptide resistance in enterococci and coagulase-negative staphylococci (CoNS) and to determine the susceptibilities of the identified glycopeptide-resistant isolates to dalbavancin., Methods: Twenty-two medical laboratories participated in the study conducted in 2016/17 by the Paul-Ehrlich-Society for Chemotherapy. Each laboratory was asked to collect 30 Enterococcus spp. (limited to Enterococcus faecalis and Enterococcus faecium) and 30 CoNS isolates consecutively from hospitalised patients with a proven or suspected infection., Results: A total of 1285 isolates were collected, comprising 364 E. faecalis, 291 E. faecium and 630 CoNS. No E. faecalis isolates (0%) but 76 E. faecium isolates (26.1%) were vancomycin-resistant, of which 21 showed the VanA type and 55 the VanB type. The proportion of vancomycin-resistant strains among E. faecium isolates from patients in intensive care units (21.6%) was significantly lower than that from patients on regular wards (30.5%). Among the CoNS, 67 isolates (10.6%) were teicoplanin-resistant but none were vancomycin-resistant, with resistance only detected in Staphylococcus epidermidis (12.2%), Staphylococcus haemolyticus (17.9%) and Staphylococcus hominis (13.2%). Dalbavancin at ≤0.25 mg/L inhibited all VanB-type enterococci and 95.5% of teicoplanin-resistant CoNS., Conclusion: The level of glycopeptide resistance in E. faecalis remains very low in Germany but achieved 26% in E. faecium and was >10% in CoNS. Dalbavancin appears to be a feasible option for treating infections caused by VanB-type vancomycin-resistant E. faecium and teicoplanin-resistant CoNS., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: This multicenter study aimed to assess the performances of gradient diffusion (GD) method in comparison to broth microdilution (BMD) method for susceptibility testing of dalbavancin, daptomycin, vancomycin, and teicoplanin., Methods: Minimum Inhibitory Concentrations (MICs) were retrospectively determined concomitantly by BMD and GD methods, for 93 staphylococci and enterococci isolated from clinical samples. BMD was considered as the gold standard. Essential (EA) and categorical agreements (CA) were calculated. Discordant categorical results were categorized as major (ME) and very major errors (VME)., Results: EA and CA were 95.7% and 96.8%, 82.8% and 100%, 97.8% and 96.8%, and 94.6% and 95.7% for dalbavancin, daptomycin, vancomycin, and teicoplanin respectively. Concerning dalbavancin, 3 ME without any VME were observed and discrepancies were low (≤ to 2 two-fold dilutions) between both methods. VME were noted in 1 and 3 cases for vancomycin and teicoplanin, respectively, and resulted from 1 two-fold dilution discrepancy in each case. EA was lower for daptomycin. When they were discrepant, BMD MICs were systematically higher than GD ones. Nevertheless, no categorical discrepancy was noted., Conclusions: GD appears as an acceptable and convenient alternative for dalbavancin, vancomycin, and teicoplanin MICs determination. Our study also emphasizes how achieving accurate daptomycin MICs remains challenging.

Drug combinations may have a crucial role in treating infections due to multidrug resistant Acinetobacter spp. One suggested combination is colistin with teicoplanin. The effect of colistin on Acinetobacter spp. outer membrane can permit teicoplanin to its target in the cell wall. The aim of this study was to evaluate the synergistic activity of colistin and teicoplanin combination against 29 multidrug resistant isolates of Acinetobacter spp. The antimicrobial activity of colistin alone and in combination with teicoplanin was assessed using MIC and time-kill assays. The combination of 1 mg/l colistin and 10 mg/l teicoplanin showed in vitro synergism against all tested Acinetobacter isolates except one (Acinetobacter lowffii). The combination of 1 mg/l colistin and 10 mg/l teicoplanin was bactericidal at 6 h against 100% of Acinetobacter baumannii isolates with no bacterial regrowth at 24 h. The same combination was bactericidal against three out of seven non-baumannii Acinetobacter isolates. The increased concentration of teicoplanin (20 mg/l) was synergistic but still not bactericidal against the four remaining isolates. The combination of colistin and teicoplanin was synergistic against all tested Acinetobacter spp It is therefore recommended that clinical trials are conducted to clarify the therapeutic potential of the combination., (© 2022. The Author(s).)

Teicoplanin is a glycopeptide antibiotic deployed to combat Gram-positive bacterial infection and has recently been associated with development of adverse drug reactions, particularly following previous exposure to vancomycin. In this study, we generated teicoplanin-specific monoclonal T-cell populations from healthy volunteers expressing HLA-A*32:01 and defined pathways of T-cell activation and HLA allele restriction. Teicoplanin-responsive T-cells were CD8+, HLA class I-restricted, and cross-reacted with the lipoglycopeptide daptomycin in proliferation and cytokine/cytolytic molecule (granzyme B, Perforin, and FasL) release assays. These data show that teicoplanin activates T-cells, which may play a role in the pathogenesis of teicoplanin-induced adverse events, in HLA-A*32:01 positive donors.

The YjgF/YER057c/UK114 (Rid) is a protein family breadth conserved in all domains of life and includes the widely distributed archetypal RidA (YjgF) subfamily and seven other subfamilies (Rid1 to Rid7). Among these subfamilies, RidA is the only family to have been biochemically well characterized and is involved in the deamination of the reactive enamine/imine intermediates. In this study, we have characterized a protein of the Rid7 subfamily, named Rid7C, in Nonomuraea gerenzanensis, an actinomycete that is characterized by the presence of two types of RNA polymerases. This is due to the coexistence in its genome of two RNA polymerase (RNAP) β chain-encoding genes, rpoB(S) (the wild-type rpoB gene) and rpoB(R) (a specialist, mutant-type rpoB gene) that controls A40926 antibiotic production and a wide range of metabolic adaptive behaviors. Here, we found that expression of rpoB(R) is regulated posttranscriptionally by RNA processing in the 5' untranslated region (UTR) of rpoB(R) mRNA and that the endoribonuclease activity of Rid7C is responsible for mRNA processing, thereby overseeing several tracts of morphological and biochemical differentiation. We also provide evidence that Rid7C may be associated with RNase P M1 RNA, although M1 RNA is not required for rpoB(R) mRNA processing in vitro , and that Rid7C endoribonuclease activity is inhibited by A40926, suggesting the existence of a negative feedback loop in A40926 production and a role of the endogenous synthesis of A40926 in the modulation of biochemical differentiation in this microorganism. IMPORTANCE The YjgF/YER057c/UK114 family includes many proteins with diverse functions involved in detoxification, RNA maturation, and control of mRNA translation. We found that Rid7C is an endoribonuclease that is involved in processing of rpoB(R) mRNA, coding for a specialized RNA polymerase beta subunit that oversees morphological differentiation and A40926 antibiotic production in Nonomuraea gerenzanensis. Rid7C-mediated processing promotes rpoB(R) mRNA translation and antibiotic production, while Rid7C endoribonuclease activity is inhibited by A40926, suggesting a role of the endogenous synthesis of A40926 in modulation of biochemical differentiation in this microorganism. Finally, we show that recombinant Rid7C copurified with M1 RNA (the RNA subunit of RNase P) from Escherichia coli extract, suggesting a functional interaction between Rid7C and M1 RNA activities.

Background: Gram-positive pathogens remain a major cause of healthcare- and community-associated infections. In particular, the dissemination of methicillin-resistant staphylococci, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE), have significantly reduced the therapeutic options, making the management of these infections even more challenging. Dalbavancin is a second-generation lipoglycopeptide approved for the treatment of moderate to severe acute bacterial skin and skin structure infections (ABSSSIs) caused by Gram-positive organisms, showing a bactericidal effect and a low propensity towards the selection of resistance over time., Aim: To evaluate the antimicrobial activity of dalbavancin and other comparators against recent clinical isolates of Gram-positive pathogens obtained from different sources and from several European countries, including countries of Southern and Eastern Europe, and Russia, where resistance rates are typically high. This study also aimed to describe the clonal relationship of MRSA strains circulating in Southern and Eastern Europe and Russia., Results: In total, 1478 isolates were collected. Study results demonstrated the excellent and stable activity of dalbavancin against Gram-positive microorganisms, including MRSA. Interestingly, dalbavancin has retained unaltered minimum inhibitory concentration (MIC 50 and MIC 90 ) values over the years, and seems to have a low propensity towards the selection of resistance., Conclusions: These data support the potential efficacy of dalbavancin against Gram-positive bacteria and uncommon Gram-positive pathogens in patients with ABSSSIs. Of note, few coagulase-negative staphylococci (CoNS) isolates were resistant to dalbavancin and susceptible to vancomycin, highlighting the importance of testing for susceptibility to dalbavancin before its administration for CoNS infections., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Teicoplanin is a natural lipoglycopeptide antibiotic with a similar activity spectrum as vancomycin; however, it has with the added benefit to the patient of low cytotoxicity. Both teicoplanin and vancomycin antibiotics are actively used in medical practice in the prophylaxis and treatment of severe life-threatening infections caused by gram-positive bacteria, including methicillin-resistant Staphylococcus aureus , Enterococcus faecium and Clostridium difficile . The expression of vancomycin Z ( vanZ ), encoded either in the vancomycin A ( vanA ) glycopeptide antibiotic resistance gene cluster or in the genomes of E. faecium , as well as Streptococcus pneumoniae and C. difficile , was shown to specifically compromise the antibiotic efficiency through the inhibition of teicoplanin binding to the bacterial surface. However, the exact mechanisms of this action and protein structure remain unknown. In this study, the three-dimensional structure of VanZ from E. faecium EnGen0191 was predicted by using the I-TASSER web server. Based on the VanZ structure, a benzimidazole based ligand was predicted to bind to the VanZ by molecular docking. Importantly, this new ligand, named G3K, was further confirmed to specifically inhibit VanZ-mediated resistance to teicoplanin in vivo.

The presence of methicillin-resistant Staphylococcus aureus (MRSA) in bone infections difficults its treatment and is a sign of concern. The aim of this study was to evaluate in vitro activity of dalbavancin on pre-established adhered cells and 24 h old biofilms of MRSA strains isolated from a human bone infection. Thirty-three MRSA were isolated from osteomyelitis episodes. The antimicrobial susceptibility of these strains was assessed by the Kirby-Bauer disc diffusion method and the presence of resistance genes was screened by PCR. MRSA planktonic minimum inhibitory concentration and minimum bactericidal concentration were assessed. Minimum biofilm eradication concentration (MBEC) was performed by the microtiter biofilm formation assay. All 33 MRSA strains were classified as multidrug-resistant strains and susceptible to dalbavancin. Dalbavancin inhibited the growth of 54.6% and 52% of strains at the concentrations of 0.05 µg/mL and 1 µg/mL, respectively. The MBEC values up to 0.4 µg/mL demonstrated that dalbavancin was active against most strains in pre-established adhered cells and 24 h old biofilms. The current results show that dalbavancin is active against adhered cells and biofilms in vitro , suggesting that this antimicrobial agent may be an option for the treatment of bone infections caused by MRSA.

Objectives: Long-acting lipoglycopeptides are promising therapeutic options in Staphylococcus aureus bone and joint infections (BJIs). This study evaluated the ability of dalbavancin to eradicate the intraosteoblastic reservoir of S. aureus, associated with BJI chronicity., Methods: Osteoblastic cells were infected with a standardized inoculum of the S. aureus reference strain HG001 and incubated for 24 h with dalbavancin, vancomycin or rifampicin using the MIC, 10×MIC, 100×MIC and/or the intraosseous concentrations reached using standard therapeutic doses (i.e. vancomycin, 10 mg/L; rifampicin, 2 mg/L; and dalbavancin, 6 mg/L). The remaining intracellular bacteria were quantified by plating cell lysates., Results: MICs of dalbavancin, vancomycin and rifampicin were 0.125, 1 and 0.004 mg/L, respectively. Dalbavancin significantly reduced the intracellular inoculum of S. aureus starting at a concentration equal to the MIC, with a significant dose effect, ranging from a reduction of 31.4% (95% CI = 17.6%-45.2%) at MIC to 51.6% (95% CI = 39.8%-63.4%) at 100×MIC compared with untreated cells. Of note, dalbavancin was the only molecule to significantly reduce the intraosteoblastic inoculum at low concentration (MIC). At intraosseous concentrations, dalbavancin reduced the intracellular inoculum by 49.6% (95% CI = 45.1%-54.1%) compared with untreated cells (P < 0.001), with no significant difference compared with vancomycin (38.1%; 95% CI = 19.2%-57.0%; P = 0.646), and was less efficient than rifampicin (69.0%; 95% CI = 63.2-74.8; P < 0.001)., Conclusions: Dalbavancin was able to decrease the intraosteoblastic S. aureus inoculum by 50% at intraosseous concentrations reached during standard human therapeutic dosing, with no difference compared with vancomycin, and remained less efficient than rifampicin. However, it was the only molecule significantly active at low concentration., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

We report a case of osteomyelitis due to methicillin-resistant Staphylococcus aureus (MRSA) that is also non-susceptible to vancomycin, dalbavancin, ceftaroline, and ceftobiprole, in the absence of exposure to the latter three antibiotics. It was isolated from a patient with a 26-year history of cranial surgeries and episodes of osteomyelitis. Whole-genome sequencing was performed. It was found to belong to ST247 and the mecA gene was detected within the SSCmec type I (1B) gene cassette that lacked the E447K mutation known to produce resistance to ceftobiprole and ceftaroline. However, mutations in other genes related to resistance to these antibiotics were found., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: The COVID-19 pandemic has dramatically challenged the national health systems worldwide in the last months. Dalbavancin is a novel antibiotic with a long plasmatic half-life and simplified weekly administration regimens, thus representing a promising option for the outpatient treatment of Gram-positive infections and the early discharge of hospitalized patients. Dalbavancin is approved for the treatment of acute bacterial skin and skin structure infections (ABSSSIs). Many preliminary data seem to support its use in other indications, such as osteomyelitis, prosthetic joint infections, and infective endocarditis., Areas Covered: A search in the literature using validated keywords (dalbavancin, Gram-positive infections, Gram-positive cocci, ABSSSI, intravenous treatment, and long-acting antibiotics) was conducted on biomedical bibliographic databases (PubMed and Embase) from 2004 to 30 September 2020. Results were analyzed during two consensus conferences with the aim to review the current evidence on dalbavancin in Gram-positive infections, mainly ABSSSI, osteomyelitis, and infective endocarditis, highlight the main limitations of available studies and suggest possible advantages of the molecule., Expert Opinion: The board identifies some specific subgroups of patients with ABSSSIs who could mostly benefit from a treatment with dalbavancin and agrees that the design of homogenous and robust studies would allow a broader use of dalbavancin even in other clinical settings.

Introduction. Dalbavancin was approved in Europe in 2015 for skin and soft tissue infections. Hypothesis/Gap Statement. Data on methicillin-resistant coagulase-negative staphylococci (MR-CNS) dalbavancin susceptibility are scarce. Aim. To assess the susceptibility of MR-CNS to dalbavancin and other anti-staphylococcal agents. Methodology. A total of 443 MR-CNS clinical isolates from patients hospitalized in a Greek university hospital during a 2.5-year period (January 2018 to June 2020) were included. The MICs for vancomycin, teicoplanin, linezolid and daptomycin were investigated by Etest and the MIC for dalbavancin was determined according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines in 196 isolates. The consumption of the aforementioned antimicrobials was calculated. Results. In total, 51 isolates were resistant to teicoplanin (11.5 %) and 211 (47.6 %) to linezolid; all were susceptible to vancomycin and daptomycin. Among 196 isolates tested, 32 (16.3 %) were resistant to dalbavancin. A significant increase of MIC during the study period was found for vancomycin, teicoplanin and daptomycin, while a decrease in linezolid's MIC was observed. Dalbavancin's MIC remained stable. No difference in consumption was observed among the studied anti-staphylococcal agents. Conclusion. An increase of vancomycin, teicoplanin and daptomycin MICs among MR-CNS was observed, whereas 47.6 % of isolates were non-susceptible to linezolid. Dalbavancin retains excellent potency against MR-CNS, even in the presence of non-susceptibility to other anti-staphylococcal antibiotics.