Skin Structure Infections Research Articles

Activity of the Novel Aminomethylcycline KBP-7072 and Comparators against 1,057 Geographically Diverse Recent Clinical Isolates from the SENTRY Surveillance Program, 2019.

ABSTRACTKBP-7072 is a novel broad-spectrum tetracycline (aminomethylcycline) antibacterial in clinical development (oral and intravenous formulations) for the treatment of acute bacterial skin and skin structure infections, community-acquired bacterial pneumonia, and complicated intra-abdominal infections. KBP-7072 is active against many of the World Health Organization priority pathogens. In this study, KBP-7072 and tetracycline class comparators were susceptibility tested against 1,057 geographically diverse surveillance isolates from 2019 according to Clinical and Laboratory Standards Institute (CLSI) guidelines. KBP-7072 demonstrated potent in vitro activity against Gram-positive and Gram-negative bacterial pathogens. KBP-7072 was active against Staphylococcus aureus (MIC50/90, 0.06/0.12 mg/liter), methicillin-resistant S. aureus (MIC50/90, 0.06/0.12 mg/liter), S. lugdunensis (MIC50/90, 0.03/0.03 mg/liter), and other coagulase-negative staphylococci (MIC50/90, 0.06/0.25 mg/liter). KBP-7072 was active against Enterococcus faecalis (MIC50/90, 0.03/0.06 mg/liter) and vancomycin-susceptible and -nonsusceptible E. faecium (MIC50/90, 0.03/0.03 mg/liter); Streptococcus pneumoniae (MIC50/90, ≤0.015/0.03 mg/liter), including penicillin- and tetracycline-resistant strains; S. agalactiae (MIC50/90, 0.03/0.06 mg/liter), including macrolide-resistant strains; S. pyogenes (MIC50/90, 0.03/0.03 mg/liter); and viridans group streptococci, including S. anginosus group (MIC50/90, ≤0.015/0.03 mg/liter) isolates. KBP-7072 inhibited 90.2% (MIC50/90, 0.25/2 mg/liter) of all Enterobacterales isolates, including expanded-spectrum β-lactamase-phenotype strains at ≤2 mg/liter. KBP-7072 demonstrated potent activity against Acinetobacter baumannii-calcoaceticus species complex and Stenotrophomonas maltophilia isolates (MIC50/90 values, 0.5/1 mg/liter), Haemophilus influenzae (MIC50/90, 0.12/0.25 mg/liter; 100.0% inhibited at ≤0.25 mg/liter), and Moraxella catarrhalis (MIC50/90, 0.06/0.06 mg/liter). Based on MIC90 values, KBP-7072 in vitro activity was generally superior to that the other tetracycline class comparators tested. The potent activity of KBP-7072, including resistant organism groups, merits further clinical investigation in infections where these organisms are likely to occur.

Clinical use of lefamulin: A first-in-class semisynthetic pleuromutilin antibiotic.

Lefamulin is a novel antibiotic agent within the pleuromutilin derivative class approved for the treatment of community-acquired bacterial pneumonia (CABP) by the United States Food and Drug Administration and the European Commission in 2019 and 2020, respectively. The objective of this article is to provide a summary of clinically relevant data underlying lefamulin and to provide recommendations for its place in therapy. In vitro data establish lefamulin's activity against a number of Gram-positive, Gram-negative and atypical organisms relevant in the treatment of CABP, including Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Legionella pneumophila, Mycoplasma pneumoniae and Chlamydophila pneumoniae. Two phase-3 studies, the Lefamulin Evaluation Against Pneumonia trials, established non-inferiority of lefamulin against moxifloxacin in the treatment of CABP, including the sequential transition from intravenous to oral therapy and across a broad set of patient demographics and severities. Pooled and post hoc analyses have confirmed these effects for a variety of subgroups and secondary endpoints. Real-world study data post-approval have largely not yet emerged for lefamulin, and there is a need for further investigation into safety/efficacy for off-label indications such as acute bacterial skin and skin structure infections and sexually transmitted infections. Further data regarding tolerability, particularly with long-term use, as well as the emergence of resistance over time, are still undefined.

Use of oral tetracyclines in the treatment of adult outpatients with skin and skin structure infections: Focus on doxycycline, minocycline, and omadacycline

Oral tetracyclines have been used in clinical practice for over 60 years. One of the most common indications for use of oral tetracyclines is for treatment of adult outpatients with skin and soft infections (SSTIs), including acute bacterial skin and skin structure infections (ABSSSIs). The 2014 Infectious Diseases Society of America (IDSA) skin and soft tissue guideline strongly recommends sulfamethoxazole/trimethoprim, clindamycin, and tetracyclines as oral treatment options for patients with purulent SSTIs, especially when methicillin‐resistant Staphylococcus aureus is of clinical concern. Despite the long‐standing use of tetracyclines, practice patterns indicate that they are often considered after other guideline‐concordant oral options for the treatment of patients with SSTIs. Clinicians may therefore be less familiar with the clinical data associated with use of commercially available tetracycline agents for treatment of patients with SSTI. This review summarizes the literature on the use of oral tetracyclines (ie, doxycycline, minocycline, and omadacycline) for the treatment of adult patients with SSTIs. As part of this review, we describe their common mechanisms of resistance, susceptibility profiles against common SSTI pathogens, pharmacokinetics and pharmacodynamics, and comparative clinical data.

Comparative efficacy of delafloxacin for complicated and acute bacterial skin and skin structure infections: results from a network meta-analysis

BackgroundDelafloxacin is a novel fluoroquinolone with broad antibacterial activity against pathogens causing acute bacterial skin and skin structure infections (ABSSSI). This network meta-analysis (NMA) was conducted to evaluate the relative efficacy of delafloxacin versus other comparators used for managing patients with ABSSSI.MethodsA systematic literature review was conducted to identify randomised controlled trials (RCTs) evaluating adults (≥ 18 years) with ABSSSI, complicated SSSI (cSSSI), complicated skin and soft tissue infections (cSSTI) or severe cellulitis with pathogen of gram-positive, gram-negative, or mixed aetiology. OVID MEDLINE®, Embase, Epub Ahead of Print, Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews were searched from inception through 12 April 2019. A feasibility assessment was conducted, followed by an NMA, which was run in a Bayesian framework. The interventions included in the NMA encompassed monotherapy or combination therapies of amoxicillin/clavulanate, ampicillin/sulbactam, ceftaroline, ceftobiprole, dalbavancin, daptomycin, delafloxacin, fusidic acid, iclaprim, linezolid, omadacycline, oxacillin + dicloxacillin, standard therapy, tedizolid, telavancin, tigecycline, vancomycin, vancomycin + aztreonam and vancomycin + linezolid.ResultsA feasibility assessment was performed and evidence networks were established for composite clinical response (n = 34 studies), early clinical response (n = 16 studies) and microbiological response (n = 14 studies) in the overall study population, composite clinical response (n = 4 studies) in obese subpopulation and for composite clinical response (n = 18 studies) and microbiological response (n = 14 studies) in patients with methicillin-resistant Staphylococcus aureus (MRSA) infection. Delafloxacin performed significantly better than fusidic acid, iclaprim, vancomycin, and ceftobiprole for composite clinical response. Delafloxacin was comparable to dalbavancin, daptomycin, fusidic acid, iclaprim, linezolid, omadacycline, tedizolid, vancomycin, vancomycin + aztreonam and vancomycin + linezolid in the analysis of early clinical response, whereas for microbiological response, delafloxacin was comparable to all interventions. In the obese subpopulation, the results favoured delafloxacin in comparison to vancomycin, whilst the results were comparable with other interventions among the MRSA subpopulation.ConclusionsDelafloxacin is a promising new antibiotic for ABSSSI demonstrating greater improvement (composite clinical response) compared to ceftobiprole, fusidic acid, iclaprim, telavancin and vancomycin and comparable effectiveness versus standard of care for all outcomes considered in the study.

Antibiotics in the pipeline: a literature review (2017-2020).

IntroductionAntimicrobial resistance (AMR) is an emerging global threat. It increases mortality and morbidity and strains healthcare systems. Health care professionals can counter the rising AMR by promoting antibiotic stewardship and facilitating new drug development. Even with the economic and scientific challenges, it is reassuring that new agents continue to be developed.MethodsThis review addresses new antibiotics in the pipeline. We conducted a review of the literature including Medline, Clinicaltrials.org, and relevant pharmaceutical companies for approved and in pipeline antibiotics in phase 3 or new drug application (NDA).ResultsWe found a number of new antibiotics and reviewed their current development status, mode of action, spectra of activity, and indications for which they have been approved. The included studies from phase 3 clinical trials were mainly utilized for the treatment of acute bacterial skin and skin structure infections, community-acquired bacterial pneumonia, and pneumonia acquired in the healthcare settings. The number of these agents is limited against high priority organisms. The identified antibiotics were based mainly on previously known molecules or pre-existing antimicrobial agents.ConclusionThere are a limited number of antibiotics against high priority organisms such as multi-drug-resistant Pseudomonas aeruginosa, and carbapenem-resistant Enterobacteriaceae. New antimicrobial agents directed against the top priority organisms as classified by the World Health Organization are urgently needed.

Dalbavancin.

Dalbavancin is a long-acting antimicrobial agent with an excellent in vitro activity against Gram-positive pathogens, including staphylococcal biofilms. The unusually long terminal half-life ranging from 149 to 250 hours in human subjects, allows a weekly dose. Currently is indicated in acute bacterial skin and skin structure infections (ABSSSIs), but in real-life clinical practice it has already been used successfully and safely in other infections, especially as consolidation therapy.

Use of Dalbavancin in Skin, Bone and Joint Infections: A Real-Life Experience in an Italian Center.

Dalbavancin is a lipoglycopeptide approved for the treatment of acute bacterial skin and skin structure infections (ABSSSI). The aim of the study was to evaluate the efficacy and safety in all patients who received at least one administration of dalbavancin. Methods: We carried out a retrospective study of the use of dalbavancin in 55 patients at the Azienda Ospedaliera Ospedali Riuniti Umberto I (Ancona, Italy) from February 2017 to May 2020 and compared “on label” and “off label” use of dalbavancin in ABSSSI and non-ABSSSI. Results: A total of 55 patients were included in the study. The median age was 61 years; 51% had ABSSSI; 24% had prosthetic joint infections, and 14% had osteomyelitis. A total of 53% received a single 1500 mg infusion of dalbavancin, and 18% received a second dose 14 days later; 24% of patients received further doses at 14-day intervals. In 91% of cases, patients achieved clinical objectives with dalbavancin: 96% of patients with ABSSSI and 69% of those with prosthetic joint infections. Conclusions: Dalbavancin was shown to have an excellent tolerability profile and to be a highly successful therapeutic approach even in those cases treated “off-label”.

A Review on Meropenem

Meropenem is a new Carbapenem antibacterial agent with wide spectrum of activity for intravenous administration. It is synthetic derivative of Thienamycin. Three analogues of Meropenem are evaluated and active against 18 bacterial strains. Meropenem causes rapid bacterial cell death by covalently binding to penicillin binding proteins (PBS). Structural modification at C-2 position, produced double promoiety prodrug of Meropenem and increases bioavailability of oral administration. Other forms of drug such as liposome and nanoparticles are also available with enhanced absorption. 14C labelled Meropenem prepared from 14C Dimethylamine hydrochloride is used for the analysis of M. tuberculosis transpeptidase. ICI213,689 is the only metabolite of Meropenem and it is inactive. Meropenem penetrates well into the body fluids and tissues including cerebrospinal fluid. Its bioavailability is 100% on intravenous administration. Hence it is used in the treatment of meningitis, febrile neutropenia, anthrax and various other skin and skin structure infections. Dosage reduction is required in patient with reduced renal function but not in hepatic impairment. Seizures, gastrointestinal haemorrhage are observed in patients. Vabmoere is the combination of Meropenem and Vaborbactam which is active against the Carbapenem resistant Enterobacteriacea. Meropenem is an effective broad-spectrum antibacterial drug for the treatment of wide range of infection including polymicrobial infection in both children and adult.

Population Pharmacokinetics, Exposure-Response, and Probability of Target Attainment Analyses for Tedizolid in Adolescent Patients with Acute Bacterial Skin and Skin Structure Infections.

ABSTRACTTedizolid phosphate is an oxazolidinone antibacterial agent approved for the treatment of Gram-positive acute bacterial skin and skin structure infections (ABSSSIs) in patients aged ≥12 years. To support the use of tedizolid phosphate in adolescents with ABSSSIs, a population pharmacokinetic (PK) model, developed using adult and pediatric data, was updated to include PK data from a phase 3 clinical trial (PN012) that evaluated the safety and efficacy of once-daily oral or intravenous 200-mg tedizolid phosphate treatment in adolescents (12 to <18 years) with ABSSSIs, along with emerging data from a phase 1 trial (PN013) in children (2 to <12 years). Updated PK parameter estimates remained similar to those of the previous model. Body weight was a statistically significant covariate on clearance and volume parameters, with no clinically meaningful effects on exposure in adolescents. Tedizolid exposures in adolescents from PN012 were slightly higher with largely overlapped area under the concentration-time curve distribution compared with adults from previous phase 2 and 3 trials. The probability of PK/pharmacodynamic target attainment at the MIC susceptibility breakpoint of 0.5 μg/ml for Staphylococcus and Streptococcus sp. was 100%. As most participants from the PN012 trial were cured, no significant exposure-efficacy relationship was identified. Tedizolid exposures were similar between participants with and without a safety event from PN012; no clear relationship was detected between exposure and safety. Despite lower body weight and higher exposures in adolescents, safety profiles in adolescents were similar those in adults. These results support the 200-mg, once-daily intravenous or oral dose of tedizolid phosphate in adolescents with ABSSSIs.

Health-Related Quality of Life as Measured by the 36-Item Short Form Survey Among Adults With Acute Bacterial Skin and Skin Structure Infections who Received Either Omadacycline or Linezolid in a Phase 3 Double-Blind, Double-Dummy Clinical Trial.

This analysis of data from a Phase 3 study of adults with acute bacterial skin and skin structure infections showed that successful oral treatment with omadacycline (n = 368) or linezolid (n = 367) was associated with improvement in health-related quality of life.

In vitro activity of ceftaroline and other antimicrobial agents against Gram positive bacterial isolates: Descriptive study from a university hospital

PurposeCeftaroline is a novel antibiotic approved by USA Food and Drug Administration (FDA) for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). It has potent in vitro activity against Staphylococci, including methicillin-resistant strains, whose incidence is increasing worldwide and they are often difficult to treat. The present study was done to investigate the susceptibility of methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant coagulase-negative Staphylococcus (MR-CoNS) to ceftaroline and other antimicrobial agents in patient samples and to evaluate clinical profile of these patients. MethodsAll consecutive, nonduplicate isolates of MRSA and MR-CoNS recovered from patient samples between June 2020 to December 2020 were included in the study. Species identification was done by Matrix Assisted Laser Desorption Ionization Time of Flight Mass Spectromtery (MALDI-TOF-MS) (BioMérieux, France). Antimicrobial sensitivity of ceftaroline and other comparator antimicrobials was done as per the Clinical and Laboratory Standards Institute (CLSI, 2020). Statistical Package for the Social Sciences (IBM-SPSS) software (Version 25) was used for statistical study. ResultsTotal 134 clinical isolates of the study consisted of MR-CoNS (115 isolates; 85.8%) and MRSA (19 isolates; 14.2%).89.5% MRSA isolates were sensitive to ceftaroline. 44.3% and 32.2% MR-CoNS isolates had ceftaroline MIC ≤1 ​μg/ml and MIC ​= ​2–4 ​μg/ml respectively. ConclusionsCeftaroline exhibited potent in vitro activity against both MRSA and MR-CoNS in the study.

Ceftaroline Fosamil for Treatment of Pediatric Complicated Skin and Soft Tissue Infections and Community-Acquired Pneumonia.

Community-acquired pneumonia (CAP)/community-acquired bacterial pneumonia (CABP) and complicated skin and soft tissue infection (cSSTI)/acute bacterial skin and skin structure infection (ABSSSI) represent major causes of morbidity and mortality in children. β-Lactams are the cornerstone of antibiotic treatment for many serious bacterial infections in children; however, most of these agents have no activity against methicillin-resistant Staphylococcus aureus (MRSA). Ceftaroline fosamil, a β-lactam with broad-spectrum in vitro activity against Gram-positive pathogens (including MRSA and multidrug-resistant Streptococcus pneumoniae) and common Gram-negative organisms, is approved in the European Union and the United States for children with CAP/CABP or cSSTI/ABSSSI. Ceftaroline fosamil has completed a pediatric investigation plan including safety, efficacy, and pharmacokinetic evaluations in patients with ages ranging from birth to 17 years. It has demonstrated similar clinical and microbiological efficacy to best available existing treatments in phase III–IV trials in patients aged ≥ 2 months to < 18 years with CABP or ABSSSI, with a safety profile consistent with the cephalosporin class. It is also approved in the European Union for neonates with CAP or cSSTI, and in the US for neonates with ABSSSI. Ceftaroline fosamil dosing for children (including renal function adjustments) is supported by pharmacokinetic/pharmacodynamic modeling and simulations in appropriate age groups, and includes the option of 5- to 60-min intravenous infusions for standard doses, and a high dose for cSSTI patients with MRSA isolates, with a ceftaroline minimum inhibitory concentration of 2–4 mg/L. Considered together, these data suggest ceftaroline fosamil may be beneficial in the management of CAP/CABP and cSSTI/ABSSSI in children.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40272-021-00468-w.

Anti-MRSA Cephalosporin versus Vancomycin-Based Treatment for Acute Bacterial Skin and Skin Structure Infection: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

This systematic review and meta-analysis of randomized controlled trials (RCTs) compared the clinical efficacy and safety of anti-MRSA cephalosporin and vancomycin-based treatment in treating acute bacterial skin and skin structure infections (ABSSSIs). PubMed, Embase, Cochrane Central Register of Controlled Trials, Turning Research into Practice, and ClinicalTrials.gov databases were searched for relevant articles from inception to 15 June 2020. RCTs comparing the clinical efficacy and safety of anti-MRSA cephalosporin with those of vancomycin-based regimens in treating adult patients with ABSSSIs were included. The primary and secondary outcomes were clinical response at the test-of-cure assessments and risk of adverse events (AEs), respectively. Eight RCTs were enrolled. The clinical response rate was not significantly different between anti-MRSA cephalosporin and vancomycin-based treatments (odds ratio [OR], 1.05; 95% CI, 0.90–1.23; I2 = 0%). Except for major cutaneous abscesses in which anti-MRSA cephalosporin-based treatment was associated with a lower clinical response rate than vancomycin-based treatment (OR, 0.62; 95% CI, 0.40–0.97; I2 = 0%), other subgroup analyses according to the type of cephalosporin (ceftaroline or ceftobiprole), type of infection, and different pathogens did not show significant differences in clinical response. Anti-MRSA cephalosporin-based treatment was only associated with a higher risk of nausea than vancomycin-based treatment (OR, 1.41; 95% CI, 1.07–1.85; I2 = 0%). In treating ABSSSIs, the clinical efficacy of anti-MRSA cephalosporin is comparable to that of vancomycin-based treatment, except in major cutaneous abscesses. In addition to nausea, anti-MRSA cephalosporin was as tolerable as vancomycin-based treatment.

LB780 Risk factors predicting Cellulitis diagnosis in a prospective cohort undergoing dermatology consultation in the Emergency Department

Cellulitis is a skin and skin-associated structure infection with many clinical mimickers called pseudocellulitis. Dermatology consultation is considered the gold standard for diagnosis. A prospective cohort of adult patients presenting to the emergency department with concern for lower extremity cellulitis received dermatology consultation with conferral of a final diagnosis. Patients with signs of complicated cellulitis, such as abnormal vital signs, or infection overlying hardware, animal bites, or sites of recent surgery were excluded.

Ceftaroline Dosage Optimized for Pediatric Patients With Renal Impairment Using Physiologically Based Pharmacokinetic Modeling.

Ceftaroline fosamil is a fifth-generation cephalosporin approved as a treatment for adults and children with community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections. However, its pharmacokinetics have not been fully evaluated in children with renal impairment. This study aimed to propose proper ceftaroline dosages optimized for the renally impaired pediatric population using physiologically based pharmacokinetic (PBPK) modeling. A PBPK model of ceftaroline was established and verified to simulate its disposition in the healthy population and renally impaired adults and to predict the exposure in renally impaired pediatric patients. Consistency was confirmed between simulated and observed data after intravenous administration of various ceftaroline regimens; fold errors were within the 2-fold error range. Among 6-year-old children, healthy subjects had 1.5-fold, 2-fold, and 2.6-fold lower areas under the plasma concentration-time curve (AUCs) than the moderate, severe, and end-stage renally impaired patient groups, respectively; among 1-year-old children, healthy subjects had 1.5-fold, 2.1-fold, and 2.5-fold lower AUCs than the respective renally impaired patient groups; among 1-month-old children, healthy subjects had 1.5-fold, 1.8-fold, and 2.2-fold lower AUCs than the respective renally impaired patient groups. The proposed dosage should be adjusted to 8, 6, and 5mg/kg every 8hours for patients aged ≥2 years to <18 years (≤33kg) with moderate, severe, and end-stage renal impairment, respectively; 5, 4, and 3mg/kg every 8hours for patients aged 2 months to <2 years with moderate, severe, and end-stage renal impairment, respectively; 4, 3.5, and 2.5mg/kg every 8hours for patients 0 to <2 months of age with moderate, severe, and end-stage renal impairment, respectively. Furthermore, pharmacodynamic investigations demonstrated that adequate antimicrobial effects were attained at the proposed doses in 3 age groups. Hence, our PBPK model can be an effective tool to support ceftaroline dosage proposals for renally impaired pediatric patients.

Contezolid: First Approval.

Contezolid 康替唑胺 (Youxitai 优喜泰®), an orally administered oxazolidinone antibacterial agent, is being developed by Shanghai MicuRx Pharmaceutical Co., Ltd. for the treatment of multidrug-resistant (MDR) Gram-positive bacterial infections, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci. In June 2021, it was approved by the National Medical Products Administration of China for the treatment of complicated skin and soft tissue infections (cSSTI), including, but not limited to, methicillin-susceptible S. aureus, MRSA, Streptococcus pyogenes and Streptococcus agalactiae. The recommended dosage of contezolid is 800 mg (i.e. two 400 mg tablets) every 12 h for 7–14 days. Contezolid is also undergoing clinical development for acute bacterial skin and skin structure infections (ABSSSI) in the USA, and for diabetic foot infections. This article summarizes the milestones in the development of contezolid leading to this first approval for the treatment of cSSTI.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40265-021-01576-0.

EVALUATION OF ANTIBIOTIC EFFICACY AND PRESCRIBING PATTERN IN SKIN AND SKIN STRUCTURE INFECTIONS AT A TERTIARY CARE TEACHING HOSPITAL

Objective: This study was carried out to evaluate the efficacy and prescribing pattern of antibiotics in the skin and skin structure infections (SSTIs) at tertiary care teaching hospital. Methods: In this prospective observational study, an attempt was made to evaluate the efficacy and prescribing pattern of antibiotics. Subjects were selected according to the inclusion and exclusion criteria and patient case sheets were analyzed for patient demographic details, results of physical examination and laboratory parameters, and prescription pattern. Results: Cellulitis was the most common skin and skin structure infection among the subjects, followed by an ulcer. Few patients showed discomforts such as pain, swelling, and purulent discharge. Surgical procedure has been done in 76 patients. Out of 99 patients, 11 patients showed a prolonged length of stay (LOS) (≥16 d), which is an indication of the poor efficacy of antibiotics. Intravenous to oral antibiotic therapy switch was seen in 47 patients, which indicates that the patient’s condition was improved. The mean length of hospital stay was 8.79 d. The majority of patients have been discharged within 15 d. Cephalosporins were the most frequently prescribed class of antibiotics in patients with skin and soft tissue infections. Metronidazole was the most frequently used antibiotic as monotherapy followed by cefuroxime. Piperacillin+Tazobactam was the most frequently used combination antibiotic. This study finds that the antibiotic treatment was efficacious in the majority of the patients. Conclusion: This study finds that the antibiotic treatment was efficacious in the majority of the patients.

Real-World Use of Dalbavancin in the Era of Empowerment of Outpatient Antimicrobial Treatment: A Careful Appraisal Beyond Approved Indications Focusing on Unmet Clinical Needs.

Dalbavancin is a novel, long-acting lipoglycopeptide characterized by a long elimination half-life coupled with excellent in vitro activity against multidrug-resistant Gram-positives. Although it is currently approved only for the treatment of acute bacterial skin and skin structure infections, an ever-growing amount of evidence supports the efficacy of dalbavancin as a long-term therapy in osteomyelitis, prosthetic joint infections, endocarditis, and bloodstream infections. This article provides a critical reappraisal of real-world use of dalbavancin for off-label indications. A search strategy using specific keywords (dalbavancin, osteomyelitis, endocarditis, long-term suppressive therapy, bloodstream infection, pharmacokinetic/pharmacodynamic profile) until April 2021 was performed on the PubMed-MEDLINE database. As for other novel antibiotics, a conundrum between approved indications and potential innovative therapeutic uses has emerged for dalbavancin as well. The promising efficacy in challenging scenarios (i.e., osteomyelitis, endocarditis, prosthetic joint infections), coupled with the unique pharmacokinetic/pharmacodynamic properties, makes dalbavancin a valuable alternative to daily in-hospital intravenous or outpatient antimicrobial regimens in the treatment of long-term Gram-positive infections. This makes dalbavancin valuable in the current COVID-19 scenario, in which hospitalization and territorial medicine empowerment are unavoidable.

Development, validation, and application of an LC–MS/MS method for the quantification of the novel antibiotic drug lefamulin (Xenleta®) and its main metabolite 2R-hydroxy lefamulin in human plasma

Lefamulin (Xenleta®) is a first in-class systemic pleuromutilin antibiotic that inhibits bacterial protein synthesis and selectively binds to a highly conserved region of the peptidyl transferase center of the bacterial 50S ribosomal subunit. A total of twenty-five Phase 1 clinical studies, one Phase 2 study in acute bacterial skin and skin structure infections (ABSSSI), and two pivotal Phase 3 studies in adults with community acquired bacterial pneumonia (CABP) have been completed. Xenleta® (lefamulin) has been approved by the FDA on August 19, 2019, by Health Canada on July 10, 2020, and by the EMA on July 28, 2020 for the oral and IV treatment of CABP in adults.For and during the clinical development, simple, sensitive, precise, and selective LC–MS/MS methods were developed and validated, first for lefamulin alone and later for the simultaneous quantification of lefamulin and its main metabolite 2R-hydroxy lefamulin in human plasma.Chromatographic separation in the current method was achieved on a reverse phase C18 column using gradient elution at a flowrate of 500 μL/min consisting of a mobile phase of water (A) and methanol (B) each containing 0.1 % formic acid (v/v) with a run time of 8.0 min. The detection and quantification of the analytes were performed on AB Sciex Triple Quad 5500 using multiple reaction monitoring operated in positive electrospray ionization mode after a simple plasma protein precipitation cleanup and dilution. The method was linear over the concentration range of 1.00−1 000 ng/mL (r ≥ 0.999) for lefamulin und 1.00–500 ng/mL (r ≥ 0.999) for 2R-hydroxy lefamulin. No significant matrix effects and a good extraction recovery were observed. The within- and between-run precision and accuracy were within the acceptable limits, and both analytes were found to be stable throughout the short term, long term, and freeze thaw stability studies. This current validated method was successfully applied in five Phase 1 and two Phase 3 studies.

Rigorous antibiotic stewardship in the hospitalized elderly population: saving lives and decreasing cost of inpatient care.

BackgroundThere is limited literature evaluating the effect of antibiotic stewardship programmes (ASPs) in hospitalized geriatric patients, who are at higher risk for readmissions, developing Clostridioides difficile infection (CDI) or other adverse outcomes secondary to antibiotic treatments.MethodsIn this cohort study we compare the rates of 30 day hospital readmissions because of reinfection or development of CDI in patients 65 years and older who received ASP interventions between January and June 2017. We also assessed their mortality rates and length of stay. Patients were included if they received antibiotics for pneumonia, urinary tract infection, acute bacterial skin and skin structure infection or complicated intra-abdominal infection. The ASP team reviewed patients on antibiotics daily. ASP interventions included de-escalation of empirical or definitive therapy, change in duration of therapy or discontinuation of therapy. Treatment failure was defined as readmission because of reinfection or a new infection. A control group of patients 65 years and older who received antibiotics between January and June 2015 (pre-ASP) was analysed for comparison.ResultsWe demonstrated that the 30 day hospital readmission rate for all infection types decreased during the ASP intervention period from 24.9% to 9.3%, P < 0.001. The rate of 30 day readmissions because of CDI decreased during the intervention period from 2.4% to 0.30%, P = 0.02. Mortality in the cohort that underwent ASP interventions decreased from 9.6% to 5.4%, P = 0.03. Lastly, antibiotic expenditure decreased after implementation of the ASP from $23.3 to $4.3 per adjusted patient day, in just 6 months.ConclusionsRigorous de-escalation and curtailing of antibiotic therapies were beneficial and without risk for the hospitalized patients 65 years and over.