Treatment Of Acute Bacterial Skin And Skin Structure Infections Research Articles

Single Intravenous Dose Dalbavancin Pathway for the Treatment of Acute Bacterial Skin and Skin Structure Infections: Considerations for Emergency Department Implementation and Cost Savings

BackgroundA pathway for the treatment of acute bacterial skin and skin structure infections (ABSSSI) with a single intravenous (IV) dose of dalbavancin was previously shown to reduce hospital admissions and shorten inpatient length of stay (LOS). ObjectivesTo describe pathway implementation at the emergency department (ED) and evaluate cost-effectiveness of a single-dose dalbavancin administered to ED patients who would otherwise be hospitalized to receive usual care with multidose IV antibiotics. MethodsThe dalbavancin pathway was previously implemented at 11 U.S. EDs (doi:10.1111/acem.14258). Patients with ABSSSI, without an unstable comorbidity or infection complication requiring complex management, were treated with a single dose of dalbavancin. At the emergency physicians’ discretion, patients were either discharged and received outpatient follow-up or were hospitalized for continued management. A decision analytic cost-effectiveness model was developed from the U.S. healthcare's perspective to evaluate costs associated with the dalbavancin pathway compared with inpatient usual care. Costs (2021 USD) were modeled over a 14-day horizon and included ED visits, drug costs, inpatient stay, and physician visits. One-way and probabilistic sensitivity analyses examined input parameter uncertainty. ResultsDriven largely by the per diem inpatient cost and LOS for usual care, the dalbavancin pathway was associated with savings of $5133.20 per patient and $1211.57 per hospitalization day avoided, compared with inpatient usual care. The results remained robust in sensitivity and scenario analyses. ConclusionThe new single-dose dalbavancin ED pathway for ABSSSI treatment, which was previously implemented at 11 U.S. EDs, offers robust cost savings compared to inpatient usual care.

Clinical, organizational, and pharmacoeconomic perspectives of dalbavancin vs standard of care in the infectious disease network.

The therapeutic approach to the patient with acute bacterial skin and skin structure infection (ABSSSI) and complicated infections often involves the early transition from intravenous to oral therapy (early switch) or early discharge. Our study aimed to evaluate sustainable and innovative care models that can be transferred to community healthcare and the economic impact of dalbavancin therapy vs Standard of Care (SoC) therapy for the treatment of ABSSSI and other Gram-positive infections including those by multidrug-resistant organisms. We also described the organization of an infectious disease network that allows optimizing the treatment of ABSSSI and other complex infections with dalbavancin. We retrospectively studied all patients treated with dalbavancin in the University Hospital "S. Anna" of Ferrara, Italy, between November 2016 and December 2022. The clinical information of each patient was collected from the hospital's SAP database and used to evaluate the impact of dalbavancin in early discharge with reduction of length of stay promoting dehospitalization and in improving adherence to antibiotic therapy. A total of 287 patients (165 males and 122 females) were included in the study of which 62 were treated with dalbavancin. In 13/62 patients dalbavancin was administered in a single dose at the completion of therapy to facilitate early discharge. Assuming a 12-day hospitalization required for the treatment of ABSSSI or to complete the treatment of osteomyelitis or spondilodiscitis, the treatment with dalbavancin results in a cost reduction of more than €3,200 per single patient compared to SoC (dancomycin, linezolid or vancomycin). Dalbavancin has proven to be a valid therapeutic aid in the organization of a territorial infectious disease network given its prolonged action, which allows the dehospitalization with management of even patients with complex infections in outpatient parenteral antimicrobial therapy.

The efficacy of dalbavancin and impact on hospitalization and treatment costs in patients with ABSSSI.

Acute bacterial skin and skin structure infections (ABSSSIs) represent a common and costly healthcare burden, accounting for millions of annual infections and billions of dollars in healthcare expenditures. Dalbavancin is a long-acting glycopeptide antibiotic that has demonstrated efficacy and safety in the treatment of ABSSSIs. This review article will examine the efficacy of dalbavancin and focus on its impact on the hospital length of stay and costs associated with management of these infections.

Target attainment of intravenous lefamulin for treatment of acute bacterial skin and skin structure infections.

Lefamulin is a pleuromutilin antibiotic approved for the treatment of community-acquired bacterial pneumonia (CABP). Its spectrum of activity, good penetration into soft tissues and low rates of cross-resistance also make lefamulin a potentially valuable option for treatment of acute bacterial skin and skin structure infections (ABSSSIs). A Phase 2 trial of lefamulin for ABSSSI indicated similar efficacy of 100 and 150 mg q12h IV dosing regimens. In the present study, the potential of lefamulin for this indication was further evaluated from a translational pharmacokinetic/pharmacodynamic perspective. PTA was determined for various dosages using Monte Carlo simulations of a population pharmacokinetic model of lefamulin in ABSSSI patients and preclinical exposure targets associated with bacteriostasis and a 1-log reduction in bacterial count. Overall target attainment against MSSA and MRSA was calculated using lefamulin MIC distributions. Overall attainment of the bacteriostasis target was 94% against MSSA and 84% against MRSA for the IV dosage approved for CABP (150 mg q12h). Using the same target, for the 100 mg q12h regimen, overall target attainment dropped to 68% against MSSA and 50% against MRSA. Using the 1-log reduction target, overall target attainment for both regimens was <40%. Lefamulin at the currently approved IV dosage covers most Staphylococcus aureus isolates when targeting drug exposure associated with bacteriostasis, suggesting potential of lefamulin for the treatment of ABSSSIs. Lefamulin may not be appropriate in ABSSSI when rapid bactericidal activity is warranted.

The Potential Utility of Single-Dose Long-Acting Intravenous Antibiotics for Acute Bacterial Skin and Skin-Structure Infections in the Emergency Department.

Acute bacterial skin and skin-structure infections (ABSSSIs) are frequent clinical presentations to emergency departments (EDs) across the nation that can require substantial resources to treat due to several factors. These include an increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) as the causative organism, limited availability of oral antibiotics that treat ABSSSIs secondary to MRSA, absorption and pharmacodynamic concerns with oral therapy, and regimen adherence. In patients who are unable to tolerate oral therapy, or are unable to adhere to prescribed antibiotics, inpatient admission for intravenous (IV) antibiotics may be necessary. Although inpatient IV antibiotics used to treat MRSA, such as vancomycin, are relatively inexpensive, hospital admission itself incurs significant associated costs. The introduction of the long-acting lipoglycopeptides, dalbavancin and oritavancin, has many potential advantages for the treatment of ABSSSIs including one- or two-dose regimens, allowing patients to receive their dose in the ED or infusion center and avoid inpatient admission altogether. Existing data have borne out these results, demonstrating that these agents can significantly reduce the length of hospital stay and the overall treatment cost of ABSSSIs. However, as these agents have nontraditional therapeutic regimens compared with alternative IV and oral agents that require consistent dosing, it is imperative to have decision support tools in place to ensure that this therapy is utilized in appropriate patients with ABSSSIs and that its true benefits can be realized for both the patient and the health care system.

Outpatient care concept and potential inpatient cost savings associated with the administration of dalbavancin – A real-world data and retrospective cost analysis

BackgroundThe treatment of acute bacterial skin and skin structure infections (ABSSSI) usually involves intravenous (i.v.) antibiotics requiring hospitalisation and increasing hospital costs. Since 2014, dalbavancin is approved for ABSSSIs treatment. However, evidence of its health economic impact on the German healthcare system is still limited. MethodsDiagnosis-related groups (DRG) based cost analysis was used to evaluate real-world data (RWD) from a German tertiary care center. All patients treated with i.v. antibiotics in the Department of Dermatology and Venereology at the University Hospital of Cologne were included to detect potential cost savings from a payer perspective. Thus, for the inpatient care German diagnosis-related groups (G-DRG) tariffs, length of stay (LOS), main- and secondary DRG-diagnoses and for the outpatient setting ‘Einheitlicher Bewertungsmaßstab’ (EBM) codes were evaluated. ResultsThis retrospective study identified 480 inpatient cases treated for ABSSSI between January 2016 until December 2020. Complete cost data were available for 433 cases and the detection of long-hospital-stay patients based on surcharges for exceeding the upper limit LOS led to 125 cases (29%) including 67 females (54%) and 58 males (46%) with an overall mean age of 63.6 years; all treated for International Classification of Diseases (ICD −10th revision) code A46 ‘erysipelas’. A sub-analysis focussed on DRG J64B with a total of 92 cases exceeding the upper limit LOS by a median of 3 days resulted in a median surcharge of €636 (mean value €749; SD €589; IQR €459-€785) per case. In comparison, we calculated outpatient treatment costs of approximately €55 per case. Thus, further treatment of these patients in an outpatient setting before exceeding the upper limit LOS might result in a cost-saving potential of approximately €581 per case. ConclusionDalbavancin appears a cost-efficient option to reduce inpatient treatment costs by transitioning to an outpatient setting of patients with ABSSSI potentially exceeding the upper limit LOS.

REDS study: Retrospective effectiveness study of dalbavancin and other standard of care of the same IV antibiotic class in patients with ABSSSI.

Acute bacterial skin and skin-structure infections (ABSSSIs) are a common source of morbidity in both the community and hospital settings. The current standard of care (SoC) requires multiple-dose intravenous (IV) regimens, which are associated with high hospitalisation rates, concomitant event risks and costs. Dalbavancin is a lipoglycopeptide, long-acting antibiotic that is effective against Gram-positive microorganisms, including methicillin-resistant Staphylococcus aureus (MRSA). Dalbavancin allows treatment of ABSSSIs with a single-shot IV administration or once weekly for 2 weeks, enabling clinicians to treat patients in an outpatient setting or to shorten the length of hospital stay. This multicentre, observational, retrospective study compared hospitalised patients who received dalbavancin and patients treated with the three most used IV antibiotics of the same or similar class: vancomycin, teicoplanin and daptomycin. The primary outcome was the time to discharge after starting the study antibiotics. The primary endpoint, time to discharge from the study therapy start, was measured for both groups: the median number of days was 6.5 in the dalbavancin group vs. 11.0 days in the SoC group. Moreover, in subpopulations of patients receiving one or more concomitant antibiotics active for Gram-positives, MRSA and patients with the most prevalent comorbidity (i.e., diabetes), the advantage of dalbavancin in terms of length of stay was confirmed, with a halved time to discharge or more. Safety data on dalbavancin were consistent with data collected in clinical trials. No serious adverse drug reactions related to dalbavancin were reported and most of them were classified as skin and subcutaneous tissue disorders. One serious ADR was reported for daptomycin. Although the analysis was only descriptive, it can be concluded that dalbavancin may enable a remarkable reduction in length of hospital stay, also confirming the clinical effectiveness and good safety profile demonstrated in clinical trials in a real-world setting.

Dalbavancin Boosts the Ability of Neutrophils to Fight Methicillin-Resistant Staphylococcus aureus.

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

1385. Pathway with single-dose long-acting intravenous antibiotic dalbavancin is a cost-saving alternative to usual inpatient care of acute bacterial skin and skin structure infections (ABSSSI)

Abstract Background Acute bacterial skin and skin structure infections (ABSSSI) are a common type of bacterial infection, with the cost of hospitalization being the main contributing factor to overall treatment costs. Two pragmatic clinical trials (Table 1) demonstrated that a new treatment pathway in which patients are treated with the intravenous (IV) long-acting antibiotic, dalbavancin, reduced hospital admission rates and length of stay (LOS) in hospitalized patients. The objective of this study is to evaluate the cost-effectiveness of a single dose of dalbavancin administered in the emergency department (ED) compared with IV antibiotics for appropriate patients who would otherwise be admitted to hospital and receive usual care such as vancomycin or daptomycin. Table 1.References of the Two Pragmatic Clinical Trials Methods A decision-analytic cost-effectiveness model was developed from the perspective of the US healthcare system. The population was ABSSSI patients presenting at the ED, who would be eligible to receive IV antibiotic infusion. Patients can receive IV treatment in the ED, and then discharged or followed by hospital admission for continued management (Fig. 1). A 14-day time horizon was used, representing the typical duration of ABSSSI management. Hospital admission rates and LOS were from the two clinical trials. Cost included ED visits, drug cost, inpatient stay, and physician visits. Input parameter uncertainty was examined via one-way and probabilistic sensitivity analyses. Figure 1.Decision Analytic Model Structure Results Providing dalbavancin in the ED resulted in $4,848 savings per patient (2021 USD). The drug cost of dalbavancin treatment was offset by a mean reduction of 4.24 days LOS per patient, which translated as $1,144 savings per hospitalization day avoided. One-way sensitivity analyses demonstrated that the key drivers were the cost of inpatient hospital stay and the LOS with usual care; however, none of the sensitivity analyses resulted in the new pathway being more costly (Fig. 2). Dalbavancin was cost saving in 100% of simulated scenarios. Figure 2.One-way Sensitivity Analysis Conclusion These results could help guide the management of ABSSSI by shifting care for appropriate patients from the inpatient to the outpatient setting where patients can be managed successfully, thereby freeing up hospital resources and reducing the total costs of ABSSSI treatment. Disclosures FRANK LOVECCHIO, DO, MPH, ABBVIE: Speaker|NIH: Grant/Research Support Alasdair D. Henry, PhD, AbbVie: Grant/Research Support Quan V. Doan, PharmD, AbbVie: Advisor/Consultant|AbbVie: Grant/Research Support|Allergan: Advisor/Consultant|Allergan: Grant/Research Support John L. Lock, PharmD, Abbvie: Employee|Abbvie: Stocks/Bonds Rosie D. Lyles, MD, MHA, MSc, AbbVie: AbbVie Employee|AbbVie: Stocks/Bonds Xiaolan Ye, PhD, AbbVie Inc.: AbbVie Employee|AbbVie Inc.: Stocks/Bonds.

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.

Skin infections in Europe: a retrospective study of incidence, patient characteristics and practice patterns

Acute bacterial skin and skin structure infections (ABSSSIs) are associated with considerable morbidity and a heavy healthcare burden. The primary objectives of this two-phase study were to determine the incidence of skin infections and ABSSSIs in hospitalized patients (Phase A), and to describe the characteristics and treatment of hospitalized patients with ABSSSIs (Phase B). This non-interventional, retrospective study was based on data collected from adult patients hospitalized for skin infections in six European countries (Czech Republic, Greece, Italy, Portugal, Russia and Spain) between January 2014 and June 2016. In Phase A, the total hospital incidence of skin infections and ABSSSIs was 2.4 and 1.8 per 1000 patient-days, respectively. Overall, 73.6% of 50,469 hospitalizations for skin infections were for ABSSSIs. Among the 750 patients with ABSSSIs included in Phase B, Gram-positive bacteria were isolated in 24.9%, most commonly methicillin-susceptible Staphylococcus aureus (11.5%). Empirical therapy was administered to 98.1% of patients, most often with a penicillin, with or without a β-lactamase inhibitor (42.1%). Complete cure was achieved in 46.5% and 34.5% of patients after initial treatment and treatment modification, respectively. Overall, 22.7% of patients had at least one additional ABSSSI-related hospitalization, 47.1% of patients visited the emergency room, 19.3% of patients visited primary care clinics, and 34.8% of patients visited a specialist. Treatment of ABSSSIs in Europe is associated with a heavy healthcare burden, highlighting the need for optimized management strategies that may reduce healthcare utilization.

Real-World Evidence of Efficacy and Safety of Levonadifloxacin (Oral and IV) in the Management of Acute Bacterial Skin and Skin Structure Infections (ABSSSI): Findings of a Retrospective, Multi-Center Study.

BackgroundAntimicrobial resistance by bacteria poses a substantial threat to the success in the treatment of acute bacterial skin and skin structure infections (ABSSSI). Levonadifloxacin is a novel benzoquinolizine subclass of quinolone which has a broad spectrum of activity, available in both oral and intravenous formulations for the treatment of skin structure infections caused by Gram-positive pathogens including methicillin-resistant Staphylococcus aureus (MRSA).Patients and methodsThis prescription event monitoring study captured data of 227 patients receiving levonadifloxacin (oral and/or IV) in a real-world setting to assess the safety and efficacy in the treatment of ABSSSI. Study outcomes were a clinical and microbial success at the end of therapy and safety was assessed based on adverse events reported.ResultsOne hundred and forty patients received IV levonadifloxacin therapy, 76 patients received oral alalevonadifloxacin, and 11 received IV followed by oral therapy. The mean duration of therapy was 7.3 days. Out of 227 patients, MRSA isolates were identified in 79 patients. Clinical success rates with oral, IV, and IV followed by oral levonadifloxacin therapy were 97.3%, 97.8%, and 100% respectively. The overall microbial success rate was 99.2% and only two patients reported two adverse events.ConclusionsThe excellent safety and efficacy profile of levonadifloxacin on oral and/or intravenous therapy, makes it a desirable treatment modality for management of ABSSSI. Unique features of levonadifloxacin such as availability of both IV and oral form, minimal drug-drug interactions, exemption from dosage adjustment in renal and hepatic impaired patients and a broad spectrum of coverage, makes it a suitable agent meeting several unmet clinical needs in contemporary patients.

Iclaprim Versus Vancomycin for the Treatment of Acute Bacterial Skin and Skin Structure Infection: A Systematic Review and Meta-analysis of Randomized Controlled Trials

This meta-analysis assessed the efficacy and safety of iclaprim compared with those of vancomycin in the treatment of acute bacterial skin and skin structure infection (ABSSSI). Only randomized controlled trials (RCTs) comparing the effect of iclaprim with vancomycin on adult patients with ABSSSIs were included. A total of 3 RCTs involving 1260 adult patients with ABSSSIs were enrolled. Iclaprim had a non-inferior clinical response rate compared with vancomycin. Similar trend was observed in the following subgroups: major cutaneous abscesses, cellulitis/erysipelas, wound infections, MRSA, MSSA, Streptococcus pyogenes infections. Finally, no differences were observed between iclaprim and vancomycin regarding the risks of any AE, drug-related AE, severe AE, discontinuation of study drug due to AE, and mortality. In conclusion, iclaprim exhibits non-inferior efficacy compared with vancomycin in the treatment of ABSSSI. Additionally, iclaprim was generally as well tolerated as vancomycin.

Radiolabeled Tedizolid Phosphate Liposomes for Topical Application: Design, Characterization, and Evaluation of Cellular Binding Capacity.

Nowadays, the incidence of acute bacterial skin and skin structure infection (ABSSSI) is increasing. The increased bioavailability and reduced drug resistance of antibiotics are crucial to obtain a more effective treatment response in these infections. These favorable properties could be achieved by different drug delivery systems such as liposomes. In this study, nanosized, radiolabeled tedizolid phosphate liposomal formulations were prepared and evaluated with their in vitro cellular binding capacity and biocompatible profile for topical treatment of ABSSSI. Liposomes were characterized by evaluation of their visual inspection, particle size (about 190-270nm), zeta potential value (around 0), and encapsulation efficiency (nearly 10%). The release rate of tedizolid phosphate from liposomes was also studied using dialysis membranes and evaluated kinetically. The stability of formulations was observed at three different temperatures and humidity conditions for 28days. Afterward, liposomes were labeled with 99mTc, and the optimal amount of reducing agent (stannous chloride) was determined as 500μg in this direct labeling procedure. All liposome formulations were successfully radiolabeled with high efficiency and exhibited high radiochemical purity (> 80%) during 6h in different media. Furthermore, the cellular bindings of liposomal formulations were evaluated in human skin fibroblast cells by measuring the radioactivity. Higher radioactivity values were obtained in CCD-1070Sk cells incubated by liposome formulations compared to sodium pertechnetate. This finding suggested that liposomal formulation increased the cellular binding of radioactivity. By the result of our study, nanosized, tedizolid phosphate encapsulated liposome formulation was found to be a favorable carrier system in the treatment of ABSSSI.

Potential role of new-generation antibiotics in acute bacterial skin and skin structure infections.

To summarize the available results of primary analyses from high-quality randomized studies of either recently approved or possible future agents for the treatment of acute bacterial skin and skin structure infections (ABSSSI). In the last 2 decades, several novel agents have been approved for the treatment of ABSSSI, that are also active against methicillin-resistant Staphylococcus aureus (MRSA). In addition to already available agents, further molecules are in clinical development that could become available for treating ABSSSI in the forthcoming future. The current and future availability of several new-generation antibiotics will allow to modulate therapeutic choices not only on efficacy but also on other relevant factors such as the combination of the drug safety profile and the comorbidities of any given patient, the expected adherence to outpatient therapy, and the possibilities of early discharge or avoiding hospitalization by means of oral formulations, early switch from intravenous to oral therapy, or single-dose administration of long-acting intravenous agents. With the advent of new-generation antibiotics, all these factors are becoming increasingly essential for tailoring treatment to individual patients in line with the principles of personalized medicine, and for optimizing the use of healthcare resources.

Lefamulin: A Novel Oral and Intravenous Pleuromutilin for the Treatment of Community-Acquired Bacterial Pneumonia.

Lefamulin is a novel oral and intravenous (IV) pleuromutilin developed as a twice-daily treatment for community-acquired bacterial pneumonia (CABP). It is a semi-synthetic pleuromutilin with a chemical structure that contains a tricyclic core of five-, six-, and eight-membered rings and a 2-(4-amino-2-hydroxycyclohexyl)sulfanylacetate side chain extending from C14 of the tricyclic core. Lefamulin inhibits bacterial protein synthesis by binding to the 50S bacterial ribosomal subunit in the peptidyl transferase center (PTC). The pleuromutilin tricyclic core binds to a pocket close to the A site, while the C14 side chain extends to the P site causing a tightening of the rotational movement in the binding pocket referred to as an induced-fit mechanism. Lefamulin displays broad-spectrum antibacterial activity against Gram-positive and Gram-negative aerobic and anaerobic bacteria as well as against atypical bacteria that commonly cause CABP. Pleuromutilin antibiotics exhibit low rates of resistance development and lack cross-resistance to other antimicrobial classes due to their unique mechanism of action. However, pleuromutilin activity is affected by mutations in 23S rRNA, 50S ribosomal subunit proteins rplC and rplD, ATP-binding cassette (ABC)-F transporter proteins such as vga(A), and the methyltransferase cfr. The pharmacokinetic properties of lefamulin include: volume of distribution (Vd) ranging from 82.9 to 202.8 L, total clearance (CLT) of 19.5 to 21.4 L/h, and terminal elimination half-life (t1/2) of 6.9-13.2 h; protein binding of lefamulin is high and non-linear. The oral bioavailability of lefamulin has been estimated as 24% in fasted subjects and 19% in fed subjects. A single oral dose of lefamulin 600 mg administered in fasted patients achieved a maximum plasma concentration (Cmax) of 1.2-1.5 mg/L with a time of maximum concentration (Tmax) ranging from 0.8 to 1.8 h, and an area under the plasma concentration-time curve from 0 to infinity (AUC0-∞) of 8.5-8.8 mgh/L. The pharmacodynamic parameter predictive of lefamulin efficacy is the free plasma area under the concentration-time curve divided by the minimum inhibitory concentration (fAUC24h/MIC). Lefamulin efficacy has been demonstrated using various animal models including neutropenic murine thigh infection, pneumonia, lung infection, and bacteremia. Lefamulin clinical safety and efficacy was investigated through a Phase II clinical trial of acute bacterial skin and skin structure infection (ABSSSI), as well as two Phase III clinical trials of CABP. The Phase III trials, LEAP 1 and LEAP 2 established non-inferiority of lefamulin to moxifloxacin in both oral and IV formulations in the treatment of CABP. The United States Food and Drug Administration (FDA), European Medicines Agency (EMA), and Health Canada have each approved lefamulin for the treatment of CABP. A Phase II clinical trial has been completed for the treatment of ABSSSI, while the pediatric program is in Phase I. The most common adverse effects of lefamulin include mild-to-moderate gastrointestinal-related events such as nausea and diarrhea. Lefamulin represents a safe and effective option for treating CABP in cases of antimicrobial resistance to first-line therapies, clinical failure, or intolerance/adverse effects to currently used agents. Clinical experience and ongoing clinical investigation will allow clinicians and antimicrobial stewardship programs to optimally use lefamulin in the treatment of CABP.

Acute Bacterial Skin and Skin-Structure Infections, efficacy of Dalbavancin: a systematic review and meta-analysis

ABSTRACT Objectives To know the efficacy of different doses of dalbavancin in acute bacterial skin and skin-structure infections (ABSSSIs) and versus other antibiotics. Methods We performed a systematic review of dalbavancin efficacy for ABSSSIs. We selected 10 clinical trials from MEDLINE and Cochrane databases for qualitative review. Of these, five trials compared one or two doses of dalbavancin versus other antibiotics such as vancomycin or linezolid. Results Treatment outcomes with other antibiotics were not significantly different versus two doses of dalbavancin (OR 1.13; 95% CI 0.75–1.71; p = 0.55) or single dose dalbavancin (OR 0.98; 95% CI 0.19–5.17; p = 0.98). One dose versus two doses of dalbavancin did not show significant differences in any of the treatment groups. In contrast, the global microbiological assessment results indicated a favorable outcome for two doses of dalbavancin compared to the single dose of dalbavancin (OR 2.96; 95% CI 1.19–7.39; p = 0.02) in both methicillin-resistant and methicillin-susceptible Staphylococcus aureus. Conclusion Either single dose or two dose dalbavancin treatment is as clinically effective as other antibiotics such as vancomycin and linezolid for the treatment of ABSSSIs. Abbreviations ABSSI: acute bacterial skin and skin-structure infection; AUC: area under the concentration-time curve; CE: clinical evaluable; CI: confidence interval; EOT: end of treatment; ITT: intention-to-treat; LOS: length of stay; MIC: minimum inhibitory concentration; MIC90: minimum concentration to inhibit growth of 90% of isolates; MR: methicillin resistant; MRSA: methicillin-resistant Staphylococcus aureus; MS: methicillin susceptible; MSSA: methicillin-susceptible Staphylococcus aureus; OPAT: Outpatient Parenteral Antimicrobial Therapy; OR: odds ratio; PI: penicillin intermediate; PR: penicillin resistant; PS penicillin susceptible; SIRS: systemic inflammatory response syndrome; SSTI: skin and soft tissue infection; TOC: test of cure; VR: vancomycin resistant; VS: vancomycin susceptible.

Tedizolid (torezolid) for the treatment of complicated skin and skin structure infections

ABSTRACT Introduction Acute bacterial skin and skin structure infections (ABSSSI) are among the most frequent infectious diseases. Recently, several new antibiotics with activity against MRSA have been approved. Tedizolid, a second-generation oxazolidinone approved for ABSSSI offers theoretical advantages over first-generation oxazolidinones. Areas covered A comprehensive online search of Medline, ClinicalTrials.gov, and conference presentations was made, selecting articles between January 2000 and April 2020. In this review, the authors discuss the chemical and microbiological properties of tedizolid, summarize its efficacy, safety, and potential role in the treatment of ABSSSI as well as the potential for future indications. Expert opinion Tedizolid has proven to be non-inferior compared to linezolid for the treatment of ABSSSI in two registrational phase III clinical trials, being well tolerated. Tedizolid exhibits antibacterial activity against the most important ABSSSI pathogens (including multidrug-resistant strains of MRSA), as well as mycobacteria and Nocardia. It appears to have a safe profile, including decreased myelotoxicity and no significant drug interactions. Preliminary studies with longer duration of therapy seem to confirm these potential benefits. Overall, tedizolid expands the newly acquired armamentarium to treat ABSSSI. The role of tedizolid for other indications is under investigation and has yet to be determined.

Role of new antibiotics in the treatment of acute bacterial skin and skin-structure infections.

To summarize the available efficacy and safety data of novel agents for treating acute bacterial skin and skin-structure infections (ABSSSI), focusing on those active against methicillin-resistant Staphylococcus aureus (MRSA). There are now several agents active against MRSA that are approved for the treatment of ABSSSI, including tedizolid, ceftaroline, dalbavancin, telavancin, oritavancin, delafloxacin, and omadacycline. In addition, iclaprim has completed phase-3 randomized clinical trials (RCTs). Considering the similar efficacy that arose from direct comparisons in phase-3 RCTs, in order to adopt the best approach for treating ABSSSI on patient-tailored basis, the different safety profiles and formulations of the different available agents should be balanced by taking into account the specific features of each treated patient in terms of baseline comorbidities, related risk of toxicity, need for hospitalization, possibility of early discharge, and expected adherence to outpatient oral therapy.

Budget Impact Analysis of Dalbavancin in the Treatment of Acute Bacterial Skin and Skin Structure Infections in Three European Countries.

Acute bacterial skin and skin structure infections (ABSSSIs) have been defined by the US Food and Drug Administration (FDA) in 2013 to include a subset of complicated skin and skin structure infections commonly treated with parenteral antibiotic therapy. Inpatient treatment of ABSSSIs involves a significant economic burden on the healthcare system. This study aimed to evaluate the economic impact on the National Health System associated with the management of non-severe ABSSSIs treated in hospitals with innovative long-acting dalbavancin compared to standard antibiotic therapy in Italy, Spain, and Austria. A budget impact analysis was developed to evaluate the direct costs associated with the management of ABSSSI from the national public health system perspective. The model considered the possibility of early discharge of patients directly from the Emergency Department (ED), after 1 night in the hospital, or after two or three nights in the hospital. A scenario with Standard of Care was compared with a dalbavancin scenario, where patients had the possibility of being discharged early. The epidemiological and cost parameters were extrapolated from national administrative databases and from a systematic literature review for each country. The analysis was conducted in a 3-year time horizon. A one-way deterministic sensitivity analysis was conducted to examine the robustness of the results. The model estimated an average annual number of patients with non-severe ABSSSI in Italy, Spain, and Austria equal to 5396, 7884, and 1788, respectively. A total annual expenditure of about €9.9 million, €13.5 million, and €3.4 million was estimated for treating the full set of ABSSSI patients in Italy, Spain, and Austria, respectively. Dalbavancin reduced the in-hospital length of stay in each country. In the first year of its introduction, dalbavancin significantly reduced the total economic burden in Italy and Spain (-€352,252 and -€233,991, respectively), while it increased the total economic burden in Austria (€80,769, 0.7% of the total expenditure for these patients); in the third year of its introduction, dalbavancin reduced the total economic burden in each Country (-€1.1 million, -€810,650, and -€70,269, respectively). The introduction of dalbavancin in a new patient pathway to treat non-severe ABSSSI could generate a significant reduction in hospitalized patients and the overall patient length of stay in hospital.