Lipoglycopeptide Antibiotic Research Articles

In silico molecular targets, docking, dynamics simulation and physiologically based pharmacokinetics modeling of oritavancin

IntroductionOritavancin is a semi-synthetic lipoglycopeptide antibiotic primarily used to treat serious infections caused by Gram-positive bacteria. The aim of this study was to elucidate possible molecular targets of oritavancin in human and microbes in relevance to its mechanism of action and model its pharmacokinetics for optimal dose selection in clinical practice.MethodsComputational methods were used in this study which include target prediction, molecular docking, molecular dynamics simulation, pharmacokinetics prediction, and physiological-based pharmacokinetics (PBPK) modeling.ResultsOritavancin was moderately soluble in water and did not permeate the blood-brain barrier. Seven molecular targets were identified in humans. Molecular docking results showed highest binding affinity of oritavancin with PI3-kinase p110-gamma subunit (−10.34 kcal/mol), followed by Acyl-CoA desaturase (−10.07 kcal/mol) and Cytochrome P450 2C19 (−8.384 kcal/mol). Oritavancin PBPK modelling in adult human showed that infusion has lower peak concentrations (Cmax) compared to bolus administration, with 1200 mg dose yielded Cmax of 16.559 mg/L, 800 mg dose yielded Cmax of 11.258 mg/L, and 200 mg over 3 days dose yielded Cmax of 7.526 mg/L. Notably, infusion gave extended half-life (t1/2) for all doses and slightly higher clearance rates compared to bolus, particularly for the 1200 mg and 800 mg doses. The results corroborated existing clinical pharmacokinetic data, and confirmed the model’s accuracy and predictive capability.ConclusionThis comprehensive computational study has provided invaluable insights into the pharmacological profile of Oritavancin, aiding its further development and optimization for clinical use.

Dalbavancin-resistant Staphylococcus epidermidis in vivo selection following a prosthetic joint infection: phenotypic and genomic characterization.

Dalbavancin is a lipoglycopeptide antibiotic with a wide spectrum of activity against Gram-positive bacteria, including MDR isolates. Its pharmacokinetic properties and administration patterns could be useful for the treatment of bone and joint infections, especially prosthetic joint infections (PJIs). We report the case of an 80-year-old man who experienced an acute periprosthetic joint infection of his right total knee arthroplasty (TKA). A DAIR procedure was done with tissue sampling, which allowed identification of a linezolid-resistant MDR S. epidermidis (LR-MDRSE) strain. The patient was then treated with dalbavancin (four injections). We studied the phenotypic and genomic evolution of the strains and plasma through concentrations of dalbavancin at different points in time. After four injections (1500 mg IV) of dalbavancin over a 6 month period, the dalbavancin MIC increased 4-fold. Calculated fAUC0-24/MIC ratios were 945, 1239 and 766.5, respectively, at Days 49, 71 and 106, assuming an MIC of 0.032 mg/L. The PFGE dendrogram revealed 97% similarity among all the isolates. These results suggest acquisition by the S. epidermidis strain of dalbavancin resistance when the patient underwent dalbavancin treatment. A 4-amino-acid deletion in the walK gene coinciding with the emergence of phenotypic resistance was revealed by WGS without any other relevant indels. Despite dalbavancin treatment with pharmacokinetic management, emerging dalbavancin resistance in S. epidermidis was observed, resulting in treatment failure. This outcome led to a prosthesis revision and long-term suppressive antibiotic therapy, with no recurrence of PJI after an 18 month follow-up.

What Place Is There for Long-Acting Antibiotics in the Management of Gram-Positive Infections? A Qualitative Cross-Sectional Study.

To identify the current practices with long half-life lipoglycopeptides (LGPs) and potential use/position of oritavancin. Despite their indication being limited to skin and soft tissue infections (SSTIs), long half-life lipoglycopeptides are mainly used off-label to treat bone and joint infections (BJIs) and infective endocarditis. Oritavancin and dalbavancin are both semisynthetic lipoglycopeptide antibiotics with activity against Gram-positive organisms. The game-changing property of these two antibiotics is their one-time dosing. Due to its shorter half-life, oritavancin might have an advantage over dalbavancin for a treatment duration of less than 2 weeks, as it could be used both in prolonged treatments of complicated patients in BJIs or administered as a single-dose treatment for Gram-positive cocci infections usually treated by a 5- to 10-day antibiotic course. These infections include urinary tract infections, bacteremias, catheter-related infections, etc. In addition to the possibility of being used as an end-of-treatment injection, oritavancin could be used as an empiric therapy treatment in the postoperative period in the context of device-associated especially prosthetic joint infections to allow for the early discharge of the patient. A qualitative survey was conducted in March 2022 including sixteen infectiologists, one internist, five hospital pharmacists, and one pharmacologist. Long half-life lipoglycopeptides contribute to changing the paradigm in the management of acute bacterial infections, as infectiologists now consider a range of indications and patient profiles for one single drug. Oritavancin strengthens the therapeutic arsenal in numerous infections from BJIs to urinary tract infections and could help to manage specific clinical situations, on top of providing potential benefits for the hospital's budget.

Rapid in vitro activity of telavancin against Bacillus anthracis and in vivo protection against inhalation anthrax infection in the rabbit model.

Inhalation anthrax is the most severe form of Bacillus anthracis infection, often progressing to fatal conditions if left untreated. While recommended antibiotics can effectively treat anthrax when promptly administered, strains engineered for antibiotic resistance could render these drugs ineffective. Telavancin, a semisynthetic lipoglycopeptide antibiotic, was evaluated in this study as a novel therapeutic against anthrax disease. Specifically, the aims were to (i) assess in vitro potency of telavancin against 17 B. anthracis isolates by minimum inhibitory concentration (MIC) testing and (ii) evaluate protective efficacy in rabbits infected with a lethal dose of aerosolized anthrax spores and treated with human-equivalent intravenous telavancin doses (30 mg/kg every 12 hours) for 5 days post-antigen detection versus a humanized dose of levofloxacin and vehicle control. Blood samples were collected at various times post-infection to assess the level of bacteremia and antibody production, and tissues were collected to determine bacterial load. The animals' body temperatures were also recorded. Telavancin demonstrated potent bactericidal activity against all strains tested (MICs 0.06-0.125 μg/mL). Further, telavancin conveyed 100% survival in this model and cleared B. anthracis from the bloodstream and organ tissues more effectively than a humanized dose of levofloxacin. Collectively, the low MICs against all strains tested and rapid bactericidal in vivo activity demonstrate that telavancin has the potential to be an effective alternative for the treatment or prophylaxis of anthrax infection.

Simulated Target Attainment of Multidose Regimens of Dalbavancin for Prolonged Durations of Therapy

Abstract Background Dalbavancin is a long-acting lipoglycopeptide antibiotic that is increasingly utilized for infections that require prolonged treatment durations despite the lack of Food and Drug Administration approval for these indications. There is no consensus regarding optimal dosing of dalbavancin for these infections and no available pharmacokinetic studies to identify optimal dosing for long-term use. Methods An in silico pharmacokinetic simulation was performed to assess the predicted dalbavancin concentration resulting from commonly utilized dosing regimens, in addition to modified regimens. The primary endpoint evaluated was days of median 24-hour free area under the curve over the minimum inhibitory concentration (AUC/MIC) >27.1, the established PK target. Results A dosing regimen of 1500 mg on day 0 and day 7 resulted in median AUC/breakpoint value above the target for 57 days (lower 95% confidence interval [CI], 37 days). A modified regimen of 1500 mg on day 0 and day 21 resulted in an additional 11 days of median AUC/breakpoint target attainment. The other standard dosing regimen modeled was 1000 mg on day 0, then 500 mg weekly for 5 doses. This regimen achieved the AUC/breakpoint target for 76 days (lower 95% CI, 59 days). This regimen was modified to 1000 mg on day 0, then 500 mg on days 14 and 28, which shortened the median effective treatment duration by 14 days but required 3 fewer doses. Conclusions These simulated results, when combined with the favorable observational data, support the use of commonly reported dalbavancin regimens for prolonged therapy durations. In addition, these pharmacokinetic/pharmacodynamic data support extending the dosing interval beyond the frequently reported weekly regimens, which should be investigated further with a clinical trial.

Head-to-head comparison of multi-dose oritavancin and dalbavancin for complicated infections: A propensity score-matched analysis

BackgroundOritavancin and dalbavancin are long-acting lipoglycopeptide antibiotics approved for the treatment of skin and skin structure infections. Recently, they have been used for outpatient antimicrobial therapy for complicated infections. No head-to-head studies exist for this purpose. ObjectiveTo compare outcomes of patients treated with multiple doses of oritavancin or dalbavancin for complicated infections. Patients and MethodsThis was a single-centre, retrospective cohort study evaluating adult patients who received two or more doses of lipoglycopeptides for complicated infections from February 2019 through December 2022. Patients receiving oritavancin were compared to dalbavancin after propensity score-matching. The primary endpoint was clinical success at 90 days. Other endpoints included: 30-day re-admission, 30-day mortality, adverse drug reactions (ADRs), and changes in white blood cell count and inflammatory markers after the first dose. ResultsAfter exclusions and propensity score-matching, 131 matched pairs (N = 262) were included in the analysis. Most patients were receiving lipoglycopeptide therapy for osteomyelitis. There was no significant difference in clinical success at 90 days in patients who received oritavancin compared to those who received dalbavancin (99 [76%] vs. 103 [79%], respectively; P = 0.556). There was no significant difference in secondary endpoints, however, there was a trend towards higher incidence of ADRs oritavancin compared to dalbavancin (9 [7%] vs. 2 [2%], respectively; P = 0.060) which led to more treatment discontinuation. ConclusionThere was no significant difference in efficacy between multi-dose oritavancin and dalbavancin for the treatment of complicated infections. Both agents were generally well tolerated; however, dalbavancin may be better tolerated when long-term treatment is warranted.

Dalbavancin is thermally stable at clinically relevant temperatures against methicillin-sensitive Staphylococcus Aureus.

Introduction: While the rate of orthopaedic infections has remained constant over the years, the burden on healthcare systems continues to rise with an aging population. Local antibiotic delivery via polymethyl methacrylate bone cement is a common adjunct in treating bone and joint infections. Dalbavancin is a novel lipoglycopeptide antibiotic in the same class as vancomycin that has shown efficacy against Gram-positive organisms when used systemically but has not been investigated as a local antibiotic. This study aims to identify whether dalbavancin is thermally stable at the temperatures expected during the polymerization of polymethyl methacrylate cement. Methods: Stock solutions of dalbavancin were prepared and heated using a polymerase chain reaction machine based upon previously defined models of curing temperatures in two clinically relevant models: a 10 mm polymethyl methacrylate bead and a polymethyl methacrylate articulating knee spacer model. Aliquots of heated dalbavancin were then transferred to be incubated at core body temperature (37 C) and analyzed at various time points up to 28 d. The minimum inhibitory concentration at which 90 % of colonies were inhibited (MIC) for each heated sample was determined against methicillin-sensitive Staphylococcus aureus (American Type Culture Collection, ATCC, 0173K) using a standard microbroth dilution assay. Results: The average MIC of dalbavancin was 1.63 against 0173K S.aureus. There were no significant differences in the relative MIC values after heating dalbavancin in either model compared to unheated control dalbavancin. Conclusions: Dalbavancin is thermally stable at the curing temperatures of polymethyl methacrylate cement and at human core body temperature over 28 d. Future in vitro and in vivo studies are warranted to further investigate the role of dalbavancin as a local antibiotic prior to its clinical use.

P03 A retrospective review of the safety and efficacy of dalbavancin at Ireland’s largest acute medical hospital

Abstract Background Dalbavancin is a second-generation lipoglycopeptide antibiotic. It is licensed in Ireland and the United Kingdom for the management of acute skin and soft tissue infections. International colleagues report treatment success in its use for patients who are unable to stay in hospital for prolonged periods and not suitable for OPAT.1 We reviewed the use of dalbavancin at St. James’s Hospital, Dublin, which is the largest hospital in Ireland with over 700 acute beds. We are located in Dublin’s inner city which experiences significant socio-economic deprivation. Methods We used the electronic patient records at St. James’s Hospital to capture all uses of dalbavancin from August 2018 to September 2022. We established baseline demographics, indication, microbiological characteristics, if there was oversight by ID/micro, safety and treatment outcomes. We considered how many hospital days were saved if a patient was changed to dalbavancin and discharged home compared with how long they would have required to stay in hospital to pursue conventional treatment. One hospital day in an acute bed is estimated to cost 800€. Results We identified 23 patients who met the inclusion criteria. Baseline demographics are shown in Table 1. The most common indication was endovascular infection (35%) and skin and soft tissue infection (35%) (Figure 1). Most patients were not bacteraemic. Staphylococcus aureus was the most common organism identified on blood culture (Figure 2). In total, 322 hospital beds were saved, which equates to 257 600 EUR. No patients had an adverse drug reaction. 100% of cases were discussed with micro or ID. Conclusions Dalbavancin is a safe and effective drug. It is another tool that can be used when caring for patients who are experiencing unstable housing and challenging social circumstances. Our experience has found 0 adverse events, 69% of patients experienced treatment success (this increases to 88.8% if we exclude those lost to follow up). This is an important finding considering 17% of indications were considered ‘on label’. Dalbavancin can save money on hospital beds and also reduces non-recyclable plastic associated with repeated doses of IV antibiotics.

Gausemycin A-Resistant Staphylococcus aureus Demonstrates Affected Cell Membrane and Cell Wall Homeostasis.

Antibiotic resistance is a significant and pressing issue in the medical field, as numerous strains of infectious bacteria have become resistant to commonly prescribed antibiotics. Staphylococcus aureus is a bacterium that poses a grave threat, as it is responsible for a large number of nosocomial infections and has high mortality rates worldwide. Gausemycin A is a new lipoglycopeptide antibiotic that has considerable efficacy against multidrug-resistant S. aureus strains. Although the cellular targets of gausemycin A have been previously identified, detailing the molecular processes of action is still needed. We performed gene expression analysis to identify molecular mechanisms that may be involved in bacterial resistance to gausemycin A. In the present study, we observed that gausemycin A-resistant S. aureus in the late-exponential phase showed an increased expression of genes involved in cell wall turnover (sceD), membrane charge (dltA), phospholipid metabolism (pgsA), the two-component stress-response system (vraS), and the Clp proteolytic system (clpX). The increased expression of these genes implies that changes in the cell wall and cell membrane are essential for the bacterial resistance to gausemycin A. In the stationary phase, we observed a decrease in the expression of genes involved in the phospholipid metabolism (mprF) and Clp proteolytic system (clpX).

Dalbavancin and moleculight in the COVID-19 pandemic

The COVID-19 Pandemic, which began in March 2020, and its associated surges, had an immense impact on our medical staff and their ability to perform their daily duties. The COVID-19 Pandemic necessitated hospital modifications, including the expansion of the Emergency Department, ICU, and Isolation units. The overwhelmed staff and overburdened ER and ICU required adjustments to deal with the Inpatient impasse. For example, temporary patient care rooms needed to be set up for the overflow of patients. The tsunami of the Pandemic almost overwhelmed our hospital. With the challenges presented to our hospital during the Pandemic, we needed a fresh perspective to our multi-disciplinary approach. Thus, we fathomed that the use and cost-effectiveness of both Dalbavancin, a long-acting lipoglycopeptide antibiotic combined with the diagnostic Moleculight Imaging Device would be a sound decision. We hypothesized that with the use of this cost-effective antibiotic in conjunction with the use of the Moleculight Imaging Device, with its fluorescent imaging, we could detect the presence of bacteria and assist our wound treatment and decision-making. A shift in patients from the Emergency Room/Inpatient Department to the Outpatient Department/Wound Care Center was made possible with the use of these two novel products.

Dalbavancin as sequential therapy for infective endocarditis due to Gram-positive organisms: a review.

Dalbavancin is a parenteral lipoglycopeptide antibiotic derived from teicoplanin, an analogue of vancomycin. It is mainly used for skin and soft tissue infections. The sustained half-life of approximately 14days makes dalbavancin a novel option for potential use as sequential treatment in infections such as infective endocarditis, which require prolonged antibiotic courses. However, only a few studies have been reported in the literature, and the use of dalbavancin remains limited.This article is a review of the currently available literature using dalbavancin for the treatment of infective endocarditis due to Gram-positive organisms. Almost all patients received dalbavancin as sequential therapy following standard-of-care antibiotics. The overall clinical efficacy of dalbavancin was approximately 90%, and it appeared to be well tolerated.

Comparative Activity of Lipoglycopeptide Antibiotics Against Gram-Positive Bacteria

Lipoglycopeptide antibiotics are semi-synthetic derivatives of glycopeptides and are characterized by a pronounced bactericidal activity against gram-positive pathogens. The aim of the study was comparative assessment of the sensitivity of gram-positive clinical isolates to lipoglycopeptide antibiotics (telavancin, dalbavancin, oritavancin). The following isolates were included in the work: methicillin-resistant Staphylococcus aureus (MRSA, n=780), methicillin-resistant coagulase-negative Staphylococcus spp. (MRCoNS, n=163), and vancomycin-resistant Enterococcus faecium (VREf, n=93). Serial dilutions were used to assess sensitivity with the addition of 0.002% polysorbate 80 to the medium. Lipoglycopeptides showed more pronounced antibacterial activity against MRSA compared to vancomycin, teicoplanin, and daptomycin, and had a MIC₅₀/MIC₉₀ (µg/ml): for telavancin — 0.06 /0.125, for dalbavancin — 0.016/0.06, and for oritavancin — 0.06/0.125. A trend towards an increase in the MIC of lipoglycopeptides and daptomycin was established in MRSA with the MIC of 2 µg/ml for vancomycin, the proportion of which was 13%. For MRCoNS, MIC₅₀ and MIC₉₀ of lipoglycopeptides did not exceed 0.06 µg/ml and 0.125 µg/ml, respectively. Oritavancin showed strong activity against VREf at MIC range of 0.03 µg/ml to 0.5 µg/ml, and at MIC₉₀ of 0.25 µg/ml. Thus, lipoglycopeptide antibiotics are a plausible alternative to vancomycin and daptomycin; they are characterized by pronounced activity and can be used to treat severe forms of staphylococcal infections.

Evaluation of Dalbavancin Use on Clinical Outcomes, Cost-Savings, and Adherence at a Large Safety Net Hospital.

Dalbavancin is a second-generation lipoglycopeptide antibiotic with activity against Gram-positive organisms. Dalbavancin is Food and Drug Administration (FDA)-approved for acute bacterial skin and soft tissue infections (ABSSTIs). There is a lack of substantial data on dalbavancin in more invasive infections, particularly in high-risk populations (patients with intravenous drug use and unstable living conditions). In this retrospective observational study, we reviewed all patients that received at least one dose of dalbavancin in an inpatient or outpatient setting at Parkland Hospital from February of 2019 to August of 2021. The demographics, type of infection, and rationale for dalbavancin were collected at the baseline. Clinical failure was measured by an avoidance of emergency department (ED) visits or hospital readmission at 30, 60, and 90 days. A separate analysis was conducted to estimate hospital, rehabilitation, or nursing facility days saved based on the projected length of treatment. 40 patients were included, and the majority were uninsured (85%), experiencing homelessness (60%), or had intravenous drug use (IDU) (57.5%). Indications for use included ABSSTIs (45%), bloodstream infection (67.5%), osteomyelitis (40%), infective endocarditis (10%), and septic arthritis (10%). Clinical failure was observed in 5 of the 40 patients (12.5%). Nonadherence to medical recommendations, a lack of source control, and ongoing IDU increased the risk of failure. Dalbavancin saved a total of 566 days of inpatient, rehabilitation, and nursing facility stays. Dalbavancin is a reasonable alternative to the standard of care in an at-risk population, offering decreased lengths of stays and cost savings. The uses of second-generation lipoglycopeptides are desirable alternatives to traditional outpatient parenteral antibiotic therapies for patients who otherwise would not qualify or for patients who desire less hospital contact in light of the COVID-19 pandemic. IMPORTANCE This study contributes additional experience to the literature of dalbavancin use in off-label indications, particularly for patients who do not qualify for outpatient parenteral antimicrobial therapy. The majority of the patient population were people who inject drugs and the uninsured. There is difficulty in tracking outcomes in this patient population, given their outpatient follow-up rates; however, we were able to track emergency room visits and readmissions throughout the majority of the local metroplex. The clinical use of dalbavancin at our institution also increased in the midst of the COVID-19 pandemic in an effort to preserve hospital resources and limit health care exposure. In addition, we are able to provide institution-specific cost-saving data with the use of dalbavancin.

1732. Single Center Dalbavancin Experience: A cost saving surprise in people with substance use disorder

Abstract Background Dalbavancin is a lipoglycopeptide antibiotic that has efficacy in the treatment of skin/soft tissue infections secondary to Gram-positive organisms. Given its long half-life, there has been increasing use for other indications including osteomyelitis, joint infections, and bacteremia. Our goal was to evaluate the indications for usage in our health system, characteristics of the patients receiving dalbavancin, and outcomes with recurrence of infection and cost to the health system. Methods A retrospective chart review was conducted reviewing all patients who were ordered dalbavancin in the Temple health system between Nov 1, 2019 to Mar 31, 2021. Charts were reviewed in Epic with data collection in REDCap. Results 34 orders for dalbavancin use were reviewed, representing 33 unique patients with 31 instances of dalbavancin administered. The majority of patients were male (79%) and had substance use disorder (88%). 97% of patients had formal ID consult. The majority of the patients were recommended dalbavancin due to concerns for adherence to prolonged oral regimens (17) or difficulties with SNF placement (19). The most common indications were bone and joint infections (16, 5 of which involved prosthesis) and bacteremia (9). 94% of patient received effective antibiotics prior to dalbavancin, with a median of 4 days. 75% of patients received their full prescribed course of dalbavancin. Only 1 adverse event was reported (itching and skin sloughing). At the time of writing, 12/23 (52%) of patients who were more than 90 days from a completed dalbavacin course returned for treatment for an infection at the same site within 90 days. Cost savings estimated from the alternate planned antibiotics and facility stay were calculated out to $1.47 million and 445 total hospital days were averted. Conclusion Our results show that dalbavancin use at our institution had minimal adverse reactions and were used to treat infections beyond skin/soft tissue infections in a population of predominantly people with substance use disorder. Our early experience with this drug uncovered potentially significant cost savings with dalbavancin due to avoided hospital days. Disclosures All Authors: No reported disclosures.

1015. Real World Use of Dalbavancin and Oritavancin for Optimized Outpatient Antimicrobial Therapy in Patients Inappropriate for Standard Therapy

Abstract Background Dalbavancin and oritavancin are long acting lipoglycopeptide antibiotics (LaLGP) approved for treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible gram-positive organisms. These antibiotics have shown promise in treatment of non-FDA approved gram-positive infections including bacteremia, endocarditis, pneumonia, and osteomyelitis. The aim of this review was to determine indication, length of therapy, treatment failures, and adverse drug events (ADE) in patients receiving LaLGP at our institution. Methods Retrospective study of adult patients that received LaLGP within an integrated health system consisting of 3 hospitals and 2 outpatient infusion centers, between July 2016 and February 2022. Data collection included dosing regimen specifics for both LaLGP and non-LaLGP, indication and justification for LaLGP use, culture results, labs, ADE, incidence of readmission and Emergency (ED)/Urgent Care presentation, and treatment failure defined as readmission or return to the ED/Urgent care within 90 days of therapy completion. Results 36 patients received LaLGP during the study period. A majority of patients received LaLGP for an indication other than ABSSSI (64%)(Table 1). Four patients were lost to follow-up but included in analysis of indication and justification for LaLGP use. Staphylococcus aureus (30% MRSA, 26% MSSA) was the most commonly identified pathogen in patients who received LaLGP for non-ABSSSI indications. Justification for use of LaLGP over standard therapy is shown in Table 2. The median duration of standard therapy prior to transitioning to LaLGP was 7 days. Table 3 shows agent selection, number of doses, and outcomes for ABSSSI indications vs non-ABSSSI indications. ABSSSI patients received a maximum of 2 doses; non-ABSSSI indications received 1-8 doses. Re-admission rates were higher in the ABSSSI group compared to non-ABSSSI while ED/Urgent care presentations were higher in non-ABSSSI indications. Conclusion LaLGP is a viable option for therapy completion after improvement is seen while on standard therapy in patients where daily outpatient antimicrobial therapy is not feasible. While LaLGP is currently only approved for ABSSSI, they appear to be safe and effective for other indications. Disclosures All Authors: No reported disclosures.

Dalbavancin During the COVID-19 Pandemic.

The COVID-19 pandemic, which started in March of 2020, and its associated surges have had an immense impact on the ability of medical staff to perform their daily activities. Thus, we sought to direct patients who had gram-positive Acute Bacterial Skin and Skin Structure Infections (ABSSSI) to our Outpatient Department/Wound Care Center for treatment. We met the challenge of the pandemic by shifting care in the treatment of ABSSSI using a new antibiotic delivery system. We examined the use and cost-effectiveness of Dalbavancin, a unique long-acting lipoglycopeptide antibiotic that is used in the treatment of acute bacterial skin and skin structure infections, during the COVID-19 pandemic. A total of 631 patients were treated in the Outpatient Department/Wound Care Center, with re-evaluation at the Wound Care Center on Day 3 post-infusion. The primary test of cure or major improvement was based on a 4- to 6-week re-assessment by the Wound Care Center Faculty (i.e., Podiatric, Vascular, Plastics, and Infectious Diseases). Treatment effectiveness was determined by examining documentation at follow-up. We also looked at the number of Outpatient Department treatments at the Wound Care Center for the periods 2018-2019 and 2020-2021. The shift of patients from the Emergency Department/Inpatient Department to the Outpatient Department/Wound Care Center was made possible by the use of the novel, streamlined, safe, Food and Drug Administration (FDA)-approved, well-tolerated antibiotic Dalbavancin. Dalbavancin is not prescribed for gram-negative infections, or for random prescribing, contamination, colonization, or prophylaxis. Dalbavancin has a low infusion reaction, low toxicity, long half-life, and low incidence of adverse reactions. Use of this medication was helpful for decreasing the inpatient burden in our facility.

Emergency department care of ABSSSI with dalbavancin infusion, direct discharge, and outpatient telemedicine follow up: a study protocol

Novel therapeutic strategies such as the long-acting lipoglycopeptide antibiotics allow for the treatment and discharge of selected emergency department (ED) patients with Acute Bacterial Skin and Skin Structure Infections (ABSSSI), who require intravenous antibiotics and would otherwise be hospitalized. The COVID-19 pandemic highlighted the need to develop strategies that may reduce hospitalization. The telehealth approach has shown success in remote management of cellulitis patients and could aid in the remote follow up of overall ABSSSI patients. This article describes a study protocol for the telemedicine follow up of patients diagnosed with ABSSSI in the ED, requiring intravenous treatment, receiving a single dalbavancin dose, and directly discharged. A telehealth system for remote follow up is evaluated as well as the possible inclusion of point-of-care ultrasound for the appropriate diagnosis of ABSSSI. The study will be conducted in compliance with regulatory requirements; and all collected data will be kept strictly confidential and in accordance with all relevant legislation on the control and protection of personal information. Dissemination of the study protocol may help increasing knowledge and awareness on this topic, with the aim of optimizing patient management, reducing hospitalization and lower the impact on healthcare associated costs.

A lipoglycopeptide antibiotic for Gram-positive biofilm-related infections.

Drug-resistant Gram-positive bacterial infections are still a substantial burden on the public health system, with two bacteria (Staphylococcus aureus and Streptococcus pneumoniae) accounting for over 1.5 million drug-resistant infections in the United States alone in 2017. In 2019, 250,000 deaths were attributed to these pathogens globally. We have developed a preclinical glycopeptide antibiotic, MCC5145, that has excellent potency (MIC90 ≤ 0.06 μg/ml) against hundreds of isolates of methicillin-resistant S. aureus (MRSA) and other Gram-positive bacteria, with a greater than 1000-fold margin over mammalian cell cytotoxicity values. The antibiotic has therapeutic in vivo efficacy when dosed subcutaneously in multiple murine models of established bacterial infections, including thigh infection with MRSA and blood septicemia with S. pneumoniae, as well as when dosed orally in an antibiotic-induced Clostridioides difficile infection model. MCC5145 exhibited reduced nephrotoxicity at microbiologically active doses in mice compared to vancomycin. MCC5145 also showed improved activity against biofilms compared to vancomycin, both in vitro and in vivo, and a low propensity to select for drug resistance. Characterization of drug action using a transposon library bioinformatic platform showed a mechanistic distinction from other glycopeptide antibiotics.

Evaluating the Use of Dalbavancin for Off-Label Indications.

(1) Background: Dalbavancin is a long-acting lipoglycopeptide antibiotic approved for skin and soft-tissue infections. Post-marketing experience suggests dalbavancin is being used for off-label indications that normally require long-term intravenous (IV) antibiotics; however, data assessing this off-label usage are limited. The purpose of this study was to evaluate the real-world efficacy, safety, and financial impact of off-label dalbavancin use. (2) Methods: This is a retrospective, observational study conducted within a 4-hospital health system. Adult patients who received dalbavancin from January 2018 to January 2021 for an off-label indication were included. The primary outcome was clinical success at 90 days. Secondary outcomes included safety (nephrotoxicity and hepatotoxicity). A pharmacoeconomic analysis was performed by comparing the cost of dalbavancin to the anticipated cost of patient stay if standard IV therapy was given. (3) Results: Forty-eight patients met study criteria. Indications included osteomyelitis (54%), endocarditis (23%), bacteremia (15%), and prosthetic joint infection (8%). The predominant organism was S. aureus (60%), with 42% caused by methicillin-resistant S. aureus. Overall, 41 (85%) patients achieved clinical success at 90 days, including 85% with osteomyelitis, 82% with endocarditis, and 86% with bacteremia. There were no instances of nephrotoxicity or hepatotoxicity. Estimated cost avoidance per patient was USD 5313 and USD 1683 if traditional IV therapy would have been completed in the hospital and skilled nursing facility, respectively. (4) Conclusion: Dalbavancin was associated with a relatively high success rate for the treatment of off-label indications and may be a cost-effective alternative to traditional IV antibiotic therapy.

Redirection of acyl donor metabolic flux for lipopeptide A40926B0 biosynthesis.

SummaryThe metabolic flux of fatty acyl‐CoAs determines lipopeptide biosynthesis efficiency, because acyl donor competition often occurs from polyketide biosynthesis and homologous pathways. We used A40926B0 as a model to investigate this mechanism. The lipopeptide A40926B0 with a fatty acyl group is the active precursor of dalbavancin, which is considered as a new lipoglycopeptide antibiotic. The biosynthetic pathway of fatty acyl‐CoAs in the A40926B0 producer Nonomuraea gerenzanensis L70 was efficiently engineered using endogenous replicon CRISPR (erCRISPR). A polyketide pathway and straight‐chain fatty acid biosynthesis were identified as major competitors in the malonyl‐CoA pool. Therefore, we modified both pathways to concentrate acyl donors for the production of the desired compound. Combined with multiple engineering approaches, including blockage of an acetylation side reaction, overexpression of acetyl‐CoA carboxylase, duplication of the dbv gene cluster and optimization of the fermentation parameters, the final strain produced 702.4 mg l‐1 of A40926B0, a 2.66‐fold increase, and the ratio was increased from 36.2% to 81.5%. Additionally, an efficient erCRISPR‐Cas9 editing system based on an endogenous replicon was specifically developed for L70, which increased conjugation efficiency by 660% and gene‐editing efficiency was up to 90%. Our strategy of redirecting acyl donor metabolic flux can be widely adopted for the metabolic engineering of lipopeptide biosynthesis.