Liquid Chromatographic Enantioseparation of Newly Synthesized Fluorinated Tryptophan Analogs Applying Macrocyclic Glycopeptides-Based Chiral Stationary Phases Utilizing Core-Shell Particles.

Due to the favorable features obtained through the incorporation of fluorine atom(s), fluorinated drugs are a group with emerging pharmaceutical importance. As their commercial availability is still very limited, to expand the range of possible candidates, new fluorinated tryptophan analogs were synthesized. Control of enantiopurity during the synthesis procedure requires that highly efficient enantioseparation methods be available. In this work, the enantioseparation of seven fluorinated tryptophans and tryptophan was studied and compared systematically to (i) develop analytical methods for enantioselective separations and (ii) explore the chromatographic features of the fluorotrytophans. For enantioresolution, macrocyclic glycopeptide-based selectors linked to core-shell particles were utilized, applying liquid chromatography-based methods. Application of the polar-ionic mode resulted in asymmetric and broadened peaks, while reversed-phase conditions, together with mobile-phase additives, resulted in baseline separation for all studied fluorinated tryptophans. The marked differences observed between the methanol and acetonitrile-containing eluent systems can be explained by the different solvation abilities of the bulk solvents of the applied mobile phases. Among the studied chiral selectors, teicoplanin and teicoplanin aglycone were found to work effectively. Under optimized conditions, baseline separations were achieved within 6 min. Ionic interactions were semi-quantitatively characterized and found to not influence enantiorecognition. Interestingly, fluorination of the analytes does not lead to marked changes in the chromatographic characteristics of the methanol-containing eluents, while larger differences were noticed when the polar but aprotic acetonitrile was applied. Experiments conducted on the influence of the separation temperature indicated that the separations are enthalpically driven, with only one exception. Enantiomeric elution order was found to be constant on both teicoplanin and teicoplanin aglycone-based chiral stationary phases (L < D) under all applied chromatographic conditions.

Cost evaluation of continuation of therapy with dalbavancin compared to standard-of-care antibiotics alone in hospitalized persons who inject drugs with severe gram-positive infections.

PURPOSE: Persons who inject drugs (PWID) are at risk for severe gram-positive infections and may require prolonged hospitalization and intravenous (IV) antibiotic therapy. Dalbavancin (DBV) is a long-acting lipoglycopeptide that may reduce costs and provide effective treatment in this population. METHODS: This was a retrospective review of PWID with severe gram-positive infections. Patients admitted from January 1, 2017, to November 1, 2019 (standard-of-care [SOC] group) and from November 15, 2019, to March 31, 2022 (DBV group) were included. The primary outcome was the total cost to the healthcare system. Secondary outcomes included hospital days saved and treatment failure. RESULTS: A total of 87 patients were included (37 in the DBV group and 50 in the SOC group). Patients were a median of 34 years old and were predominantly Caucasian (82%). Staphylococcus aureus (82%) was the most common organism, and bacteremia (71%) was the most common type of infection. Compared to the SOC group, the DBV group would have had a median of 14 additional days of hospitalization if they had stayed to complete their therapy (P = 0.014). The median total cost to the healthcare system was significantly lower in the DBV group than in the SOC group ($31,698.00 vs $45,093.50; P = 0.035). The rate of treatment failure was similar between the groups (32.4% in the DBV group vs 36% in the SOC group; P = 0.729). CONCLUSION: DBV is a cost-saving alternative to SOC IV antibiotics for severe gram-positive infections in PWID, with similar treatment outcomes. Larger prospective studies, including other patient populations, may demonstrate additional benefit.

Proactive therapeutic monitoring of dalbavancin concentrations in the long-term management of chronic osteoarticular/periprosthetic joint infections.

Here, we describe the use of proactive therapeutic drug monitoring (TDM) to individualize the optimal timing of drug injections in 16 adult patients with chronic osteoarticular infections receiving a median of 7 injections of dalbavancin (up to 12 injections in 15 months). Dalbavancin injections were repeated at medians of 39-47 days, with infusion intervals ranging from 26 to 69 days. TDM can facilitates a precise, targeted use of dalbavancin for infections requiring prolonged treatments.

Dalbavancin real-life utilization among diabetic patients suffering from infections in Italy and Spain: The DALBADIA retrospective cohort study.

OBJECTIVES: To retrospectively describe the patterns of use of dalbavancin for treating infections in diabetic patients in Italian and Spanish standard clinical practice. METHODS: DALBADIA [NCT04959799] was a multicentre, observational, retrospective cohort study, conducted in Italy and Spain. The study enrolled 97 adults with type 1 or 2 diabetes mellitus, treated with dalbavancin as per standard clinical practice for a Gram-positive bacterial infection or the Gram-positive component of a mixed infection. RESULTS: Dalbavancin was used to treat cellulitis (18/92 patients, 19.6%), followed by prosthetic joint infection (14 patients, 15.2%), endocarditis (13 patients, 14.1%), and primary bacteraemia (10 patients, 10.9%); 78/92 (84.8%) patients had Gram-positive infections only, and 14 (15.2%) had mixed infections. The most frequently isolated microorganisms were Staphylococcus aureus in 43 (55.8% of the patients with microbial isolation), 25.6% of which methicillin-resistant; Staphylococcus epidermidis in 13 (16.9%), 53.8% of which methicillin-resistant; Enterococcus faecalis in 11 (14.3%). The main reason for the dalbavancin choice was the intent to simplify the antibiotic regimen (81.5% of cases). A multidisciplinary team participated in the treatment choice process for 53 (57.6%) patients. Dalbavancin was given as first-line antibiotic in 34 (37.0%) patients and administered as one infusion in 32 (34.8%), and as two infusions in 39 (42.4%). In total, 57/62 (91.9%) eligible patients with available assessment were judged clinically cured or improved at the end of observation. CONCLUSION: In clinical practice, dalbavancin was used in diabetic patients to treat ABSSSIs and other difficult-to-treat infections with a favourable safety profile and a high rate of positive clinical responses.

Experience with dalbavancin use in various gram-positive infections within Aberdeen Royal Infirmary OPAT service.

PURPOSE: Dalbavancin, approved in 2014 for Gram-positive acute bacterial skin and skin structure infections (ABSSSI), has pharmacokinetics enabling treatment with one or two doses. Dalbavancin might be useful in outpatient parenteral antibiotic therapy (OPAT) of deep-seated infections, otherwise requiring inpatient admission. We documented our experience with pragmatic dalbavancin use to assess its effectiveness for varied indications, on- and off-label, as primary or sequential consolidation therapy. METHODS: Patients prescribed dalbavancin between 1 December 2021 and 1 October 2022 were screened for demographics of age, sex, Charlson comorbidity index (CCI), allergies, pathogens, doses of dalbavancin, other antibiotics administered and surgery. Where available, infection markers were recorded. The primary outcome was a cure at the end of treatment. Secondary outcomes included any adverse events and for those with treatment failures, response to salvage antibiotics. RESULTS: Sixty-seven per cent of patients were cured. Cure rates by indication were 93% for ABSSSI, 100% for bacteraemia, 90% for acute osteomyelitis, 0% for chronic osteomyelitis, 75% for native joint septic arthritis and 33% for prosthetic joint infection. Most bone and joint infections that were not cured did not have source control, and the goal of treatment was suppressive. Successful suppression rates were greater at 48% for chronic osteomyelitis and 66% for prosthetic joint infections. Adverse events occurred in 14 of 102 patients. CONCLUSION: This report adds to clinical experience with dalbavancin for off-label indications whilst further validating its role in ABSSSI. Dalbavancin as primary therapy in deep-seated infections merits investigation in formal clinical trials.

Rapid and Effective Treatment of Peritonitis in Peritoneal Dialysis Patients with Intravenous Dalbavancin.

BACKGROUND Peritonitis is a complication associated with peritoneal dialysis (PD), which carries a significant morbidity and mortality risk. Empiric therapy must include coverage of gram-positive organisms; vancomycin is a recommended treatment option, particularly when MRSA infection is a risk. Vancomycin is cumbersome for patients, requiring therapeutic drug monitoring and re-administration by a healthcare provider. Dalbavancin, administered as a one-time intravenous dose, is a convenient potential treatment option for PD patients to cover gram-positive organisms without the need for routine drug monitoring. CASE REPORT We present 2 patients effectively treated with dalbavancin for infectious peritonitis. The first patient, a 73-year-old woman with end-stage renal disease (ESRD) on PD, presented to the hospital with fever, elevated white blood cells (WBCs), and cloudy peritoneal fluid with elevated nucleated cell counts (88% neutrophils). This patient was given 1 dose of 1500 mg IV dalbavancin. Within 3 days, her fever resolved, WBCs returned to normal, and peritoneal fluid results improved. The second patient was a 36-year-old woman presenting to an outpatient clinic with abdominal pain and cloudy peritoneal fluid with elevated nucleated cell counts (53% neutrophils) treated with dalbavancin 1500 mg IV once. Within 4 days, this patient's pain had resolved, and peritoneal fluid results returned to baseline. No adverse effects were noted for either patient. CONCLUSIONS These cases illustrate the potential of dalbavancin as a convenient option for patients with PD-associated peritonitis. Both patients demonstrated rapid and complete response to a single dose of dalbavancin without complications. Further prospective studies are needed to establish dalbavancin as an option for peritonitis.

Dalbavancin as salvage therapy in difficult-to-treat patients for diabetes-related foot osteomyelitis.

OBJECTIVES: We aimed to describe the efficacy and safety of dalbavancin in treatment of patients with diabetes-related foot osteomyelitis with bone culture confirmation. PATIENTS AND METHODS: Between January 2019 and December 2021, all consecutive patients receiving at least one 1500 mg dose of dalbavancin for diabetes-related foot osteomyelitis were included in a retrospective study. Remission was defined as absence of relapsing infection or need for surgery at the initial or a contiguous site during 6-month follow-up from the last dose of dalbavancin. RESULTS: Thirteen patients were included. Eleven (85%) patients were surgically treated. Six (46%) patients received dalbavancin as first-line treatment and 7 (54%) as second-line treatment due to adverse events related to previous treatments. One adverse event was reported. At 6-month follow-up, 11 patients were evaluable and 9 (82%) were in remission. CONCLUSIONS: In the study, dalbavancin was well-tolerated and showed microbiological and clinical efficacy.

Effective use of a two-dose regimen of dalbavancin to treat prosthetic joint infections and spinal hardware infections.

PURPOSE: Dalbavancin is an attractive antibiotic for the treatment of Gram-positive musculoskeletal infections given its long half-life and prolonged duration in cortical bones. For certain patient populations compliance with antibiotic regimens can be problematic. Therefore, the purpose of this study was to assess the effectiveness, tolerance, and compliance of treating prosthetic joint and spinal hardware infections with a unique two-dose regimen of dalbavancin. METHODS: Identification of patients that had prosthetic joint infections and spinal hardware infections from January 1, 2017, through December 31, 2021, that had received a two-dose regimen of dalbavancin for these infections was conducted. Patient demographics, infection recurrence, compliance and adverse drug reactions to the two-dose regimen of dalbavancin were recorded. Furthermore, preserved clinical isolates from these infections were assessed for susceptibility to dalbavancin with microbroth dilutions. RESULTS: All patients were fully compliant with the two dose dalbavancin regimen and no patient had any adverse reactions to the two-dose dalbavancin regimen. Thirteen of fifteen patients (85.7%) have not had any recurrence of their infections and all preserved clinical isolates showed susceptibility to dalbavancin. DISCUSSION: The two-dose regimen of dalbavancin is an effective and attractive option in treating prosthetic joint and spinal hardware infections to forgo long term central venous access and ensure compliance. However, the use of rifampin and suppression antibiotics still needs to be considered when treating these infections. Nonetheless this study supports that a two-dose dalbavancin regimen is a viable alternative in certain clinical settings and consideration for a randomized controlled clinical trial should be entertained to prove its non-inferiority to conventional treatments.

Dalbavancin in the treatment of acute bacterial skin and skin structure and other infections: a safety evaluation.

INTRODUCTION: Dalbavancin is a second-generation lipoglycopeptide approved since 2014 to treat acute bacterial skin and skin-structure infections (ABSSSI). Dalbavancin is characterized by Gram-positive activity and novel pharmacokinetic properties allowing prolonged terminal half-life andonce weekly dosing . A good safety profile was reported in clinical trials . AREAS COVERED: Dalbavancin safety and tolerability from trials and post-marketing studies were reviewed. While most reports included predominantly ABSSSI, two clinical trials and recent observational studies have explored the use of dalbavancin for off-label indications, mainly including bloodstream and osteoarticular infections. EXPERT OPINION: The occurrence of drug-related adverse effects (AE) was similar between dalbavancin and comparators in clinical trials enrolling patients with ABSSSI. Most common AE included gastrointestinal symptoms, infusion reaction, and hypersensitivity. Low rates of drug discontinuation and serious AE were reported across studies. In the past 5 years, several observational studies have reported safety data on the use of dalbavancin, confirming its favorable safety profile. Nevertheless, data from dalbavancin off-label use, often derived from prolonged (>2 weeks) treatments with variable dosing regimens, were mainly retrospective and lacked comparators. Further research is required to allow a reliable analysis of short- and long-term dalbavancin-related AE in non-ABSSSI.

Comparative efficacy of dalbavancin alone and with rifampicin against in vitro biofilms in a pharmacodynamic model with methicillin-resistant Staphylococcus aureus.

BACKGROUND: The anti-biofilm efficacy of dalbavancin (DAL) has been evaluated in static models. The comparative activity of DAL alone and with rifampicin (RIF) against biofilm-embedded methicillin-resistant Staphylococcus aureus (MRSA) was evaluated using an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model. METHODS: Two MRSA strains (HUB-4, HUB-5) were evaluated with the Calgary Device System and the dynamic CDC-Biofilm Reactor over 144 h. Dosage regimens simulated the human PK of DAL (1500 mg, single dose), vancomycin (VAN) (1000 mg/12 h) and linezolid (LZD) (600 mg/12 h), alone and with RIF (600 mg/24 h). Efficacy was evaluated by assessing log10CFU/mL changes (ΔlogCFU/mL) and screening for resistance was conducted. RESULTS: The minimal biofilm inhibitory/eradication concentrations of DAL were 0.25/16 mg/L (HUB-4) and 0.25/8 mg/L (HUB-5). In the PK/PD analysis, DAL alone showed limited efficacy but no development of resistance. Adding RIF improved the activities of DAL, VAN, and LZD, but RIF-resistant strains appeared over time in all cases. DAL-RIF was bactericidal against HUB-4 in the absence of resistance at 72 h and 144 h (ΔlogCFU/mL: -3.54±0.83, -4.32±0.12, respectively), an effect that was only achieved by LZD-RIF at 144 h (-3.33 ± 0.66). DAL-RIF activity against HUB-5 was impaired by RIF resistance to a greater extent than other combinations and this combination had no bactericidal effect. CONCLUSIONS: The anti-biofilm efficacy of DAL was improved significantly by adding RIF. Although DAL resistance did not occur, RIF resistance appeared in all combination therapies and decreased their efficacy over time. DAL-RIF in vitro treatment appears to be a promising anti-biofilm therapy, but further studies are needed to evaluate the efficacy and risk of resistance in vivo.

A retrospective multicentre study on dalbavancin effectiveness and cost-evaluation in sternotomic wound infection treatment: DALBA SWIT Study.

OBJECTIVE: To evaluate the cost-effectiveness of dalbavancin compared with standard of care (SoC) treatment as daptomycin or teicoplanin in patients with sternal wound infections (SWI). METHODS: Multicentre retrospective study of patients diagnosed with SWI from January 2016 to December 2019 at two cardiac surgery facilities treated with dalbavancin, teicoplanin or daptomycin. Patients with SWI treated with dalbavancin were compared with SoC to evaluate resolution of infection at 90 and 180 days from infection diagnosis, length of stay (LoS) and management costs. RESULTS: 48 patients with SWI were enrolled, 25 (50%) male, median age 67 (60-73) years, Charlson index score 5 (4-7). Fifteen patients were treated with dalbavancin (31%) and 33 with SoC (69%): teicoplanin in 21 (63%), and daptomycin in 12 (37%). Staphylococcus species were the most frequent isolates (44, 92%), mostly (84%) resistant to methicillin. All patients were treated with surgical debridement followed by negative pressure wound therapy. Wound healing at day 90 and 180 was achieved in 46 (95.8%) and 34 (82.9%) of patients, respectively. A shorter length of hospitalization in patients treated with dalbavancin compared with SoC [12 (7-18) days vs 22 (12-36) days, p:0.009] was found. Treatment with dalbavancin resulted in total cost savings of €16 026 (95% CI 5976-26 076, P < 0.001). Savings were mainly related to the LoS that was significantly shorter in the dalbavancin group, generating significantly lower cost compared to SoC group. CONCLUSION: Dalbavancin treatment of sternal wound infections is effective and seems to reduce hospitalization length, leading to significantly lower costs.

Global trends of dalbavancin: A bibliometric analysis.

WHAT IS KNOWN AND OBJECTIVE?: Dalbavancin is used against gram-positive pathogens such as Staphylococcus aureus in acute bacterial skin and skin-structure infections. METHODS: Our main goal was to identify the key articles sustaining the current knowledge of this drug's therapeutic possibilities through a bibliometric analysis of the available literature. RESULTS AND DISCUSSION: On 15 March 2021, we searched the Web of Science electronically for documents that contain within its title the term "dalbavancin." We found a total of 675 documents that average 20.23 citations/publication with a density of 682.60 citations per/year, yielding an h-index of 58. After ranking them by the number of times cited, we extracted the top 100 most-cited records (T100). Number of citations/publication ranged from 13 to 231, publication years were 2002-2019, with the top-cited article published in 2014. All T100 publications were written in English. JMI Laboratories was the institution with the most articles in the T100 (22 documents), and the United States was the top country (75 documents). Five authors participated in at least five of the T100, led by Jones RN with 20 articles. Positions #1, #2, #5, and #9 were clinical trials for acute bacterial skin and skin structure infections (ABSSSI), the on-label indication for dalbavancin. Only one article in the top 10 (T10) was an off-label indication that was published in 2005 with 186 citations, and occupied the third position among the T100. Using the VOSviewer© programme, we observed that the most used keywords were: dalbavancin, lipoglycopeptide, gram-positive, osteomyelitis, vancomycin, and MRSA. WHAT IS NEW AND CONCLUSIONS?: Our study identifies the most significant research on dalbavancin, including the highest impact publications, and highlights the recent trend of dalbavancin in new therapies. The T10 articles include the most important dalbavancin clinical trials, along with other studies and reviews that support the growing role of this antibiotic in clinical use. Emphasis has been on the favourable pharmacokinetic profile that allows administration once-weekly, with minimal risk of severe adverse events.

Dalbavancin in Gram-positive periprosthetic joint infections.

OBJECTIVES: The unique properties of dalbavancin (DAL) emphasize the need to explore its clinical benefits to treat periprosthetic joint infections (PJIs). The present study aimed to compare the treatment outcome of dalbavancin with Standard of Care (SoC) in hip and knee PJIs. METHODS: Eighty-nine patients were selected for each group of this study based on our prospectively maintained PJI database. A 1:1 propensity score-matching was performed between patients who received at least two doses of dalbavancin and those who received SoC. Patients were matched based on demographics, joint, patient risk factors, Musculoskeletal Infection Society (MSIS) criteria, surgical management and type of infection. Treatment outcome was evaluated considering re-infection and re-revision rates, safety and tolerability of dalbavancin after a minimum of 1 year follow-up. RESULTS: Infection eradication was achieved in 69 (77.5%) and 66 (74.2%) patients of the DAL and SoC groups, respectively. Thirteen (14.6%) patients in the DAL group and 12 (13.5%) patients in the SoC group had an infection-related re-revision. The most prevalent microorganisms among the two groups were Staphylococcus epidermidis (32.3%), Staphylococcus aureus (13.8%) and Cutibacterium spp. (11.3%). There were significantly less Gram-positive bacteria (P = 0.03) detected in patients who received dalbavancin (17.4%) treatment compared with those treated with SoC (48.0%) in culture-positive re-revisions. CONCLUSIONS: Dalbavancin treatment for Gram-positive PJIs resulted in a similar outcome to SoC, with excellent safety and low rate of adverse effects. Dalbavancin seems to be a promising antimicrobial against PJIs by reducing the risk of Gram-positive re-infections and allowing a less frequent dosage with potential outpatient IV treatment.

Dalbavancin as an option for treatment of S. aureus bacteremia (DOTS): study protocol for a phase 2b, multicenter, randomized, open-label clinical trial.

BACKGROUND: Staphylococcus aureus bacteremia is a life-threatening infection and leading cause of infective endocarditis, with mortality rates of 15-50%. Treatment typically requires prolonged administration of parenteral therapy, itself associated with high costs and potential catheter-associated complications. Dalbavancin is a lipoglycopeptide with potent activity against Staphylococcus and a long half-life, making it an appealing potential therapy for S. aureus bacteremia without the need for durable central venous access. METHODS: DOTS is a phase 2b, multicenter, randomized, assessor-blinded, superiority, active-controlled, parallel-group trial. The trial will enroll 200 adults diagnosed with complicated S. aureus bacteremia, including definite or possible right-sided infective endocarditis, who have been treated with effective antibiotic therapy for at least 72 h (maximum 10 days) and with subsequent clearance of bacteremia prior to randomization to study treatment. Subjects will be randomized 1:1 to complete their antibiotic treatment course with either two doses of dalbavancin on days 1 and 8, or with a total of 4-8 weeks of standard intravenous antibiotic therapy. The primary objective is to compare the Desirability of Outcome Ranking (DOOR) at day 70 for patients randomized to dalbavancin versus standard of care. Key secondary endpoints include quality of life outcomes and pharmacokinetic analyses of dalbavancin. DISCUSSION: The DOTS trial will establish whether dalbavancin is superior to standard parenteral antibiotic therapy for the completion of treatment of complicated S. aureus bacteremia. TRIAL REGISTRATION: US National Institutes of Health ClinicalTrials.gov NCT04775953 . Registered on 1 March 2021.

Dalbavancin in clinical practice: a particular place for the elderly?

We investigate dalbavancin efficiency and tolerance among elderly in Grenoble-Alpes 32 university hospital. Among the 65 patients who received dalbavancin, 51% (33) were considered as old. Patients presented mainly bones and joint infections (52%), surgical site infection 34 (31%), and infective endocarditis (IE) (8%). Clinical cure was confirmed for 79% of old 35 patients at 1, 3, and 6 months. Six adverse events (9%) were reported after 36 dalbavancin's administration, but each time in combination with other antibiotics. 37 Dalbavancin had a significant effectiveness and safety profile and represents a real 38 therapeutic option in the management of deep and complex infections of elderly patients.

Experience in the use of dalbavancin in diabetic foot infection.

OBJECTIVE: To describe the clinical experience with dalbavancin in the treatment of diabetic foot infection in a multidisciplinary unit of a second level hospital. METHODS: A retrospective, descriptive study was made with all patients with diabetic foot infection treated with dalbavancin in the Diabetic Foot Unit of Hospital Universitario Fundación Alcorcón, covering the period from September 2016 to December 2019. Demographic parameters and comorbidities, characteristics of the infection and treatment with dalbavancin were recorded. The cure rate is estimated at 90 days after finishing the treatment. RESULTS: A total of 23 patients with diabetic foot infection (osteomyelitis) started treatment with dalbavancin, 19 were men and the mean age was 65 years. The microorganisms most frequently isolated for the indication of treatment with dalbavancin were Staphylococcus aureus (11) and Corynebacterium striatum (7). Dalbavancin was used as a second choice therapy in 22 cases, in 11 due to toxicity from other antibiotics. The median duration of treatment was 5 (4-7) weeks; the most frequent dose of dalbavancin (8 patients) was 1000 mg followed by 500 mg weekly for 5 weeks. 3 patients presented mild side effects (nausea and gastrointestinal discomfort). At 90 days after completion of dalbavancin therapy, 87% (20) of the patients were cured (95% CI: 65.2%-94.52%). CONCLUSION: Patients with osteomyelitis due to gram-positive microorganisms who received as part of the multidisciplinary antibiotic treatment with dalbavancin, had a high rate of cure with adequate tolerance and few side effects. Dalbavancin offers a safe alternative in treating deep diabetic foot infection.

Role of Extracellular DNA in Dalbavancin Activity against Methicillin-Resistant Staphylococcus aureus (MRSA) Biofilms in Patients with Skin and Soft Tissue Infections.

Methicillin-resistant Staphylococcus aureus (MRSA) has become the leading cause of skin and soft tissue infections (SSTIs). Biofilm production further complicates patient treatment, contributing to increased bacterial persistence and antibiotic tolerance. The study aimed to explore the efficacy of different antibiotics on biofilm-producing MRSA isolated from patients with SSTI. A total of 32 MRSA strains were collected from patients with SSTI. The MIC and minimal biofilm eradication concentration (MBEC) were measured in planktonic and biofilm growth. The study showed that dalbavancin, linezolid, and vancomycin all inhibited MRSA growth at their EUCAST susceptible breakpoint. Of the MRSA strains, 87.5% (n = 28) were strong biofilm producers (SBPs), while only 12.5% (n = 4) were weak biofilm producers (WBPs). The MBEC90 values for dalbavancin were significantly lower than those of linezolid and vancomycin in all tested strains. We also found that extracellular DNA (eDNA) contributes to the initial microbial attachment and biofilm formation. The amount of eDNA differed among MRSA strains and was significantly higher in those isolates with high dalbavancin and vancomycin tolerance. Exogenously added DNA increased the MBEC90 and protection of biofilm cells from dalbavancin activity. Of note, the relative abundance of eDNA was higher in MRSA biofilms exposed to MBEC90 dalbavancin than in untreated MRSA biofilms and those exposed to sub-MIC90. Overall, dalbavancin was the most active antibiotic against MRSA biofilms at concentrations achievable in the human serum. Moreover, the evidence of a drug-related increase of eDNA and its contribution to antimicrobial drug tolerance reveals novel potential targets for antibiofilm strategies against MRSA. IMPORTANCE Staphylococcus aureus is the most common cause of skin and soft tissue infections (SSTIs) worldwide. In addition, methicillin-resistant S. aureus (MRSA) is increasingly frequent in postoperative infections and responsible for a large number of hospital readmissions and deaths. Biofilm formation by S. aureus is a primary risk factor in SSTIs, due to a higher antibiotic tolerance. Our study showed that the biofilm-forming capacity varied among MRSA strains, although strong biofilm producers were significantly more abundant than weak biofilm producer strains. Notably, dalbavancin demonstrated a potent antibiofilm activity at concentrations achievable in human serum. Nevertheless, dalbavancin activity was affected by an increased concentration of extracellular DNA in the biofilm matrix. This study provides novel insight for designing more targeted therapeutic strategies against MRSA and to prevent or eradicate harmful biofilms.

Successful use of dalbavancin in the treatment of gram positive blood stream infections: a case series.

BACKGROUND: Dalbavancin is a semisynthetic antibiotic used as an alternative to vancomycin for skin infections and osteomyelitis. Its long half-life decreases length of hospitalizations. This study analyzes the effectiveness of Dalbavancin for bacteremia and infective endocarditis. METHODS: The authors performed a retrospective chart analysis on patients who received Dalbavancin due to being poor candidates for PICC placement, poor candidates for prolonged hospitalization, or who were leaving against medical advice. Their hospitalizations were analyzed and results were compiled using descriptive statistics. RESULTS: Our cohort had 22 patients treated with Dalbavancin for bacteremia and 1 for endocarditis. They were treated with IV antibiotics, typically a regimen of at least vancomycin and a cephalosporin, for a median of 6.5 days prior to receiving Dalbavancin. 20 received one dose, while three received two doses. 22 had confirmed culture clearance and one denied repeat culture. There were no reported side effects from the medication, no readmissions for worsened infection, and no deaths from the infection. 15 patients had follow-up visits within 90 days. CONCLUSIONS: Overall, patients responded well. The lack of readmission to the hospital indicates possible outpatient treatment. This would help decrease cost and comorbidities of long-term hospital stays. These positive results are limited by small sample size and treatment of other antibiotics prior to receiving Dalbavancin. Further research is required to accurately estimate the efficacy of Dalbavancin on bloodstream infections and endocarditis, but these results are promising especially for patients who are not candidates for long term hospitalization or outpatient IV access.

Determination of plasma protein binding of dalbavancin.

OBJECTIVES: Dalbavancin is a lipoglycopeptide with a long half-life, making it a promising treatment for infections requiring prolonged therapy, such as complicated Staphylococcus aureus bacteraemia. Free drug concentration is a critical consideration with prolonged treatment, since free concentration-time profiles may best correlate with therapeutic effect. In support of future clinical trials, we aimed to develop a reliable and reproducible assay for measuring free dalbavancin concentrations. METHODS: The ultracentrifugation technique was used to determine free dalbavancin concentrations in plasma at two concentrations (50 and 200 mg/L) in duplicate. Centrifuge tubes and pipette tips were treated for 24 h before use with Tween 80 to assess adsorption. Dalbavancin concentrations were analysed from the plasma samples (total) and middle layer samples (free) by LC/MS/MS with isotopically labelled internal standard. Warfarin served as a positive control with known high protein binding. RESULTS: Measurement of free dalbavancin was sensitive to adsorption onto plastic. Treatment of tubes and pipette tips with ≥2% Tween 80 effectively prevented drug loss during protein binding experiments. By the ultracentrifugation method, dalbavancin's protein binding was estimated to be approximately 99%. CONCLUSIONS: Dalbavancin has very high protein binding. Given dalbavancin's high protein binding, accurate measurement of free dalbavancin concentrations should be a key consideration in future exposure-response studies, especially clinical trials. Future investigations should confirm if the active fraction is best predicted by the free or total fraction.