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.

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.

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.

Clinical Pharmacokinetics and Pharmacodynamics of Dalbavancin.

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.

Antimicrobial activity of dalbavancin and comparators against Staphylococcus aureus causing pneumonia in patients with and without cystic fibrosis.

The activities of dalbavancin and comparator agents were evaluated against Staphylococcus aureus isolated from the lower respiratory tract of cystic fibrosis (CF) and non-CF patients with pneumonia. Bacterial isolates (n = 357) were collected from CF patients in 36 medical centers worldwide (2018-2019) and susceptibility tested using reference broth microdilution. Susceptibility results from these isolates were compared with those for 725 S. aureus isolates consecutively collected from non-CF patients with pneumonia from the same medical centers over the same period. Only isolates determined to be the probable cause of pneumonia were included in the study. Susceptibility profiles were very similar among isolates from CF and non-CF patients. Dalbavancin exhibited potent activity (MIC50/90, 0.03/0.03 mg/L) and complete coverage (100.0% susceptibility) against isolates from CF and non-CF patients. Ceftaroline (MIC50/90, 0.25/1 mg/L) was active against 97.8% and 98.1% of isolates from CF and non-CF patients, respectively. Oxacillin resistance (MRSA) rates were 27.7% among CF and 28.7% among non-CF patients. Among MRSA isolates from CF/non-CF patients (n = 99/208), susceptibility to ceftaroline, clindamycin, levofloxacin, and tetracycline were 91.9%/93.3%, 58.6%/64.4%, 40.4%/29.3%, and 83.8%/89.4%, respectively. Dalbavancin demonstrated high potency against S. aureus from CF and non-CF patients and may represent a valuable treatment option for CF patients with MRSA pulmonary infection.

Therapeutic potential of dalbavancin in a rat model of methicillin-resistant Staphylococcus aureus (MRSA)-osteomyelitis.

Bacterial osteomyelitis is a major clinical challenge in human and veterinary patients. This infection is an infrequent but feared complication of orthopedic surgery and is mainly caused by methicillin-resistant Staphylococcus aureus (MRSA). The aim of this study was to evaluate the efficacy of dalbavancin (dosed for either 7 or 14 days) in an MRSA-osteomyelitis tibial bone model. A total of 39 rats were included in the study. All animals received an inoculum of a clinical strain of MRSA (106 colony-forming units [CFU]) injected into the proximal tibia under general anesthesia. Dalbavancin was injected intraperitoneally for 7 or 14 days in 13 animals each; the remaining 13 animals received saline solution. After treatment, the animals were sacrificed. Infected tibiae were recovered for histological evaluation and microbiological analysis (MRSA count per gram of bone). Rats that received dalbavancin showed a statistically significant reduction of MRSA counts compared with the control group: median 0 CFU/g bone (14 days of dalbavancin) vs. 70 CFU/g bone (7 days of dalbavancin) and 1600 CFU/g bone (control). Histological evaluation showed typical signs of osteomyelitis in the control group, whereas there were no signs of bone infection in 92% of the rats that received 14 days of dalbavancin. According to this model, dalbavancin seems to have good efficacy for treating serious Gram-positive bone infections, including those caused by MRSA.

New Evidence and Insights on Dalbavancin and Wound Healing in a Mouse Model of Skin Infection.

Dalbavancin is an effective antibiotic that is widely used to treat skin infection. Our aim was to determine the effect of dalbavancin administration on wound healing compared to that of vancomycin and to elucidate if epidermal growth factor receptor (EGFR), matrix metalloproteinase 1 (MMP-1), MMP-9, and vascular endothelial growth factor (VEGF) could be involved in its therapeutic mechanism. A mouse model of methicillin-resistant Staphylococcus aureus (MRSA) skin infection was established. Mice were treated daily with vancomycin (10 mg/kg) and weekly with dalbavancin at day 1 (20 mg/kg) and day 8 (10 mg/kg). After 14 days, wounds were excised, and bacterial counts were performed. Wound healing was assessed by histological and immunohistochemical staining, followed by protein extraction and immunoblotting. Our microbiological results confirmed that both dalbavancin and vancomycin are effective in reducing the bacterial load in wounds. The dalbavancin group showed a strong effect compared with infected untreated animals and the vancomycin-treated group. The wounds treated with dalbavancin showed robust epidermal coverage with reconstitution of the regular and keratinized epidermal lining and well-organized granulation tissue with numerous blood vessels, although slightly less than that in the uninfected group. While in the vancomycin-treated group the epithelium appeared, in general, still hypertrophic, the granulation tissue appeared even less organized. We observed elevated EGFR and VEGF expression in both treated groups, although it was higher in dalbavancin-treated mice. MMP-1 and MMP-9 were decreased in uninfected tissue and in both treated tissues compared with untreated infected wounds. This study showed faster healing with dalbavancin treatment that might be associated with higher EGFR and VEGF levels.

Mammary Dysbiosis and Nipple Blebs Treated With Intravenous Daptomycin and Dalbavancin.

INTRODUCTION: Mammary dysbiosis, also known as subacute mastitis, may be associated with nipple blebs. These overlapping diagnoses represent a challenging clinical scenario during lactation. Little research has been published on etiology, management strategies, and outcomes of these concurrent diagnoses. MAIN ISSUE: We document the treatment and outcome of a patient who presented with left-breast dysbiosis and nipple blebs and whose milk culture grew multi-drug-resistant, methicillin-resistant Staphylococcus aureus. She was treated safely and effectively with intravenous daptomycin and dalbavancin. This has not been described previously in the lactation literature. MANAGEMENT: The 35-year-old lactating gravida 3, para 3 patient presented at 6 months postpartum to a breast surgery clinic with a 1-week history of worsening deep left-breast pain, blebs, and recurrent plugging. She was afebrile and she had no erythema or induration on her breast exam. A culture of her milk grew multi-drug-resistant, methicillin-resistant Staphylococcus aureus, and she was referred to infectious disease for assistance with intravenous antibiotic therapy. She continued to feed expressed milk throughout treatment and demonstrated complete resolution of symptoms 8 weeks later. CONCLUSIONS: We report that in patients with a multi-drug-resistant, methicillin-resistant Staphylococcus aureus-positive human milk culture and a clinical presentation of mammary dysbiosis and nipple blebs, intravenous daptomycin and dalbavancin may be an effective treatment.

Clinical experience with dalbavancin for the treatment of deep sternal wound infection.

OBJECTIVES: Deep sternal wound infection (DSWI) is a complication of major heart surgery with high morbidity as well as prolonged antimicrobial treatment and hospital length of stay (LoS). Dalbavancin is a new lipoglycopeptide antibiotic active against Gram-positive micro-organisms, including methicillin-resistant Staphylococcus aureus (MRSA), with a long half-life. This small case series assessed the feasibility of dalbavancin for the treatment of DSWI. METHODS: This was retrospective, observational, cohort study of patients treated with dalbavancin for DSWI over a 2-year period (March 2016 to April 2018) in two cardiac surgery departments in Italy. All patients with DSWI underwent surgical accurate debridement. Dalbavancin was administered during the hospital stay or in an outpatient facility. RESULTS: Among 15 patients enrolled in the study, MRSA was isolated in 7 (47%), methicillin-resistant Staphylococcus epidermidis in 6 (40%) and other coagulase-negative staphylococci in 2 (13%). Dalbavancin was administered by two infusions in 9 patients (60%), whereas 5 patients (33%) received a median of four doses. Fourteen patients received a first dose of 1000mg followed by 500mg, whereas one patient received two doses of 1500mg each. All patients were defined as clinically cured. The median hospital LoS was 13 days (interquartile range, 8-18 days). At 6 months after discharge, 14 patients (93%) showed no relapse of DSWI, whereas 1 patient recurred with a diagnosis of DSWI caused by another pathogen (Candida sp.). CONCLUSION: Dalbavancin may be an alternative option for DSWI caused by Gram-positive bacteria when first-line treatments are contraindicated or as salvage treatment.

Economic evaluation of the treatment of Acute Bacterial Skin and Skin Structure Infections (ABSSSIs) from the national payer perspective: introduction of a new treatment to the patient journey. A simulation of three European countries.

Background: The aim of this study was to develop a spending predictor model to evaluate the direct costs associated with the management of ABSSSIs from the National health-care provider's perspective of Italy, Romania, and Spain. Methodology: A decision-analytic model was developed to evaluate the diagnostic and clinical pathways of hospitalized ABSSSI patients based on scientific guidelines and real-world data. A Standard of Care (SoC) scenario was compared with a dalbavancin scenario in which the patients could be discharged early. The epidemiological and cost parameters were extrapolated from national administrative databases (i.e., hospital information system). A probabilistic sensitivity analysis (PSA) and one-way sensitivity analysis (OWA) were performed. Results: Overall, the model estimated an average annual number of patients with ABSSSIs of approximately 50,000 in Italy, Spain, and Romania. On average, the introduction of dalbavancin reduced the length of stay by 3.3 days per ABSSSI patient. From an economic perspective, dalbavancin did not incur any additional cost from the National Healthcare perspective, and the results were consistent among the countries. The PSA and OWA demonstrated the robustness of these results. Conclusion: This model represents a useful tool for policymakers by providing information regarding the economic and organizational consequences of an early discharge approach in ABSSSI management.

Dalbavancin treatment in a deep sternal wound MRSA infection after coronary artery bypass surgery: a case report.

BACKGROUND: A deep sternal wound infection (DSWI) can become a severe complication after cardiac surgery, with in-hospital mortality rates reaching up to 35%. Staphylococci, particularly methicillin resistant Staphylococcus aureus (MRSA), play important roles in its etiology. CASE PRESENTATION: This case report presents a patient who underwent coronary artery bypass surgery, and suffered postoperatively from a DSWI caused by MRSA. The pathogen was susceptible to vancomycin and rifampicin in vitro; however, this therapy was clinically ineffective. Both clinical improvement and MRSA eradication were achieved after surgical debridement of the wound and the intravenous administration of dalbavancin. CONCLUSIONS: We decided to administer dalbavancin because of its convenient pharmacological profile. The patient's tolerance of the antimicrobial was good, the biochemical markers of inflammation returned to the normal ranges, and the microbiological results one week after the dalbavancin administration were negative. A good clinical outcome was achieved with both the surgery and antimicrobial administration. In this case, dalbavancin was more effective in the treatment of the sternal and surrounding tissue infections caused by MRSA, when compared to vancomycin.

The role of dalbavancin in the multi-disciplinary management of wound infections in orthopaedic surgery.

Antimicrobial resistance is continuously increasing among bacterial clinical isolates (especially methicillin resistance in Staphylococcus aureus, MRSA), negatively impacting on outcomes of patients with Surgical Site Infections (SSIs). A multi-disciplinary team work is essential for SSIs prevention and for the choice of antibiotic therapy of orthopaedic SSIs. In particular, an Antibiotic Stewardship (AS) approach is recommended for preserving the activity of old and new antimicrobials. Dalbavancin is a novel antimicrobial agent, belonging to the lipoglycopeptides family, recently approved by FDA for the treatment of ABSSSIs (Acute Bacterial Skin and Skin Structure Infections) and can be considered as a candidate for the treatment of orthopaedic superficial SSIs. An antimicrobial activity directed against MRSA and other multi-resistant Gram-positive pathogens, a bactericidal effect and an extremely extended half-life are among key features of this drug. Dalbavancin gives to clinicians the option to provide an intravenous antimicrobial agent shown to be as effective as conventional therapies, without requiring prolonged admission into the hospital, drastically reducing the length of hospital stay (without reducing the treatment compliance) and total cost per patient. In this paper, we analyze general, microbiological and pharmacological features of dalbavancin, aiming at supporting clinicians while positioning this drug in the context of orthopaedic SSIs.

In vitro activity of dalbavancin and five comparator agents against common and uncommon Gram-positive organisms isolated from cancer patients.

Dalbavancin is a long acting, bactericidal lipoglycopeptide. Its in vitro activity was compared with that of vancomycin, daptomycin, linezolid, trimethoprim/sulfamethoxazole (TMP/SMX) and levofloxacin against 241 Gram-positive organisms isolated from cancer patients. The rank order of potency for the glycopeptides based on MIC90 (µg ml(-1)), that is, the concentration of antimicrobial agent required to inhibit 90% of isolates tested was dalbavancin (0.12 µg ml(-1))>daptomycin (1.0 µg ml(-1))>vancomycin (2.0 µg ml(-1)) for coagulase-negative staphylococci and Staphylococcus aureus isolates (including methicillin-susceptible (MSSA) and methicillin-resistant (MRSA) strains). Dalbavancin had potent activity against staphylococcal isolates with vancomycin MICs⩾1.0 µg ml(-1). TMP/SMX also had potent activity against staphylococci including methicillin-resistant strains, whereas levofloxacin had moderate to poor anti-staphylococcal activity. Dalbavancin also exhibited more potent activity than vancomycin and daptomycin against Bacillus spp., Corynebacterium spp., Micrococcus spp. and various streptococci (including Streptococcus pneumoniae, viridans group streptococci (VGS), beta-hemolytic streptococci and gamma-hemolytic streptococci). MBC determinations showed that dalbavancin had potent bactericidal activity against MRSA with no tolerance being detected. These data suggest that dalbavancin may be considered as an alternative to vancomycin, especially in institutions wherein a substantial proportion of infections are caused by organisms with vancomycin MICs⩾1.0 µg ml(-1).

Dalbavancin: Quantification in human plasma and urine by a new improved high performance liquid chromatography-tandem mass spectrometry method.

Dalbavancin is a novel second-generation lipoglycopeptide antibiotic with activity against broad range of Gram-positive pathogens. In order to determine the pharmacokinetics (PK) of dalbavancin in pediatric patients, a new High Performance Liquid Chromatography-Tandem Mass Spectrometry (HPLC-MS/MS) bioanalytical method has been developed for quantification of dalbavancin in plasma and in urine. The plasma method was validated for dalbavancin in the linear range from 0.5 µg/mL to 500 µg/mL using 50 µL of K(2) EDTA plasma. For dalbavancin spiked in urine, non-specific binding (NSB) of the drug to polypropylene (PP) urine collection containers was observed. The loss amounted to about 10% per transfer. After successfully establishing the collection/sampling procedure for urine by addition of Triton X-100 to the collection vessels (with a purpose of preventing NSB), the method was validated for dalbavancin in the range from 0.05 µg/mL to 50 µg/mL, using 100 µL of urine. These methods were used to quantify dalbavancin in plasma and urine of hospitalized children in a pediatric dalbavancin PK study. Eighteen percent of the total number of plasma study samples was reassayed for incurred samples reproducibility (ISR) and all the reassayed dalbavancin concentrations were within the ± 20% limits. For urine, all the collected samples were reassayed for ISR and the original dalbavancin concentration was confirmed within the ± 20% limits for 17 (94%) samples; the one remaining urine sample had its reassayed concentration confirmed within ± 25% of the original result.

Inhibition of hepatitis C virus replication by semi-synthetic derivatives of glycopeptide antibiotics.

OBJECTIVES: Some semi-synthetic derivatives of glycopeptide antibiotics have been shown to exert in vitro antiviral activity against HIV and coronaviruses. Here we report and characterize the in vitro anti-hepatitis C virus (HCV) activity of several semi-synthetic derivatives of teicoplanin aglycone. METHODS: Anti-HCV activity was analysed in: (i) three different subgenomic HCV replicon systems using a luciferase or quantitative RT-PCR (qRT-PCR) assay; and (ii) an infectious HCV cell culture system by means of qRT-PCR and immunofluorescence assays. RESULTS: Several teicoplanin aglycone derivatives elicited selective anti-HCV activity in replicons as well as infectious cell culture systems, with LCTA-949 being the most potent derivative. LCTA-949 proved, in contrast to several directly acting antivirals for HCV, efficient in clearing cells of their replicons. When LCTA-949 was combined with HCV protease or polymerase inhibitors an overall additive effect was observed. Likewise, LCTA-949 was equipotent against wild-type replicons as well as against replicons resistant to polymerase and protease inhibitors. Following up to 4 months of selective pressure, no drug-resistant replicons were selected. When combined with the HCV NS3 protease inhibitor VX-950, LCTA-949 prevented the development of VX-950-resistant variants. CONCLUSIONS: Semi-synthetic derivatives of teicoplanin aglycone constitute a novel class of HCV replication inhibitors that are not cross-resistant with various HCV protease and polymerase inhibitors and in particular are potent in clearing hepatoma cells of their replicons. This class of molecules also provides a good tool to obtain novel insights into the replication cycle of HCV and into cellular factors/processes that are crucial for viral replication.