Antimicrobial activity of dalbavancin against Gram-positive bacteria isolated from patients hospitalized with bloodstream infection in United States and European medical centers (2018–2020)

Dalbavancin and comparators were susceptibility tested against 8643 Gram-positive bacteria from 74 hospitals located in Europe and the United States by broth microdilution method. The most common organisms were Staphylococcus aureus (45.2%), Enterococcus faecalis (12.2%), and Staphylococcus epidermidis (8.9%), but rank order varied markedly by geographic region. Dalbavancin demonstrated potent activity and broad spectrum, with MIC90 values of 0.03 mg/L for Staphylococcus aureus, β-haemolytic streptococci, and viridans group streptococci; 0.06 mg/L for Enterococcus faecalis and Staphylococcus epidermidis; and 0.12 mg/L for vancomycin-susceptible Enterococcus faecium. All organisms, except vancomycin-resistant enterococci and 1 Staphylococcus haemolyticus isolate, were inhibited at ≤ 0.25 mg/L of dalbavancin.


Introduction
Bloodstream infection (BSI) includes a wide variety of syndromes caused by a range of pathogens; accordingly, BSI produces significant patient morbidity and mortality worldwide [1]. Changing pathogen distribution, antimicrobial resistance rates, and demographics may affect the epidemiology of BSI. Thus, it is important to continuously monitor trends in the pathogen frequency and antimicrobial resistance patterns of organisms causing BSI globally [2,3]. Examining microbiological trends can help when planning diagnostic approaches, treatment strategies, and prevention programs.
The International Dalbavancin Evaluation of Activity (IDEA) Program monitors the in vitro activity of dalbavancin and comparators against Gram-positive bacteria causing BSI and other infections in Europe (EU) and the United States (US). Strengths of this surveillance program include the broad geographic distribution of medical centers submitting clinical isolates and the use of reference identification and antimicrobial susceptibility testing methods at a central laboratory [4].
Dalbavancin belongs to the lipoglycopeptide class of antimicrobial agents that act by interrupting bacterial cell wall synthesis resulting in bacterial death [5]. Dalbavancin allows for convenient parenteral administration to treat acute bacterial skin and skin structure infections, either through a single dose of 1500 mg or one dose of 1000 mg followed by another dose of 500 mg a week later [6,7]. Dalbavancin was approved in the US (2014) and EU (2015) to treat adults with acute bacterial skin and skin structure infection (ABSSSI) caused by Staphylococcus aureus, including methicillin-resistant (MRSA) isolates, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus anginosus group, and vancomycin-susceptible Enterococcus faecalis. Dalbavancin is not licensed to treat patients with BSI, but it could be an important option to treat infections due to highly resistant Gram-positive cocci [8,9]. It is also important to note that ABSSSI can be secondarily complicated by bacteremia or it can be the result of skin/subcutaneous tissue seeding during bacteremia from a distant focus. Furthermore, catheter-related infections may commonly present as both ABSSSI and BSI due to the same organism. In this investigation, we evaluated dalbavancin in vitro activity and potency when tested against a large collection of Gram-positive bacteria collected from patients with BSI in US and European medical centers.

Organism collection
A total of 8643 organisms were consecutively collected (1/ patient) from 74 medical centers located in western Europe (W-EU; n = 3330; 28 centers from 10 countries: Belgium, France, Germany, Ireland, Italy, Portugal, Spain, Sweden, Switzerland, and the UK), eastern Europe (E-EU; n = 769; 13 centers from 10 countries: Belarus, Czech Republic, Greece, Hungary, Israel, Poland, Romania, Russia, Slovenia, and Turkey), and the US (n = 4544; 33 centers). Isolates determined to be clinically significant based on local guidelines were submitted to a central monitoring laboratory (JMI Laboratories, North Liberty, IA, USA) [2]. Species identification was initially performed by the participating laboratories then confirmed at JMI Laboratories by standard algorithms and/or MALDI-TOF.

Antimicrobial susceptibility testing
Isolates were susceptibility tested by broth microdilution following guidelines in the CLSI M07 document [10] with reference 96-well panels manufactured by JMI Laboratories. All isolates were tested at JMI Laboratories. Polysorbate-80 at a final concentration of 0.002% was added to the medium to test dalbavancin. Isolates with elevated dalbavancin MIC values (> 0.25 mg/L) were retested to confirm the dalbavancin MIC results. Quality assurance was performed by concurrently testing the following CLSI-recommended quality control (QC) reference strains: S. aureus ATCC 29213, E. faecalis ATCC 29212, and S. pneumoniae ATCC 49619. All QC results were within published acceptable ranges. Dalbavancin breakpoints approved by the US FDA (≤ 0.25 mg/L) [6], CLSI (≤ 0.25 mg/L) [11], and EUCAST (≤ 0.125 mg/L) [12] were applied when appropriate. US FDA, CLSI, and EUCAST breakpoint criteria were used for the comparator agents.

Discussion
Dalbavancin is a long-acting lipoglycopeptide characterized by a long elimination half-life coupled with excellent in vitro activity against multidrug-resistant Gram-positives [5,7]. Although dalbavancin has not been evaluated in clinical trials for BSI and it is currently approved only for the treatment of ABSSSI, dalbavancin has shown clinical efficacy and good tolerability for various infections. Some observational studies and real-world clinical experiences suggest the efficacy of dalbavancin for infections needing long-term treatment courses, including osteomyelitis, prosthetic joint infection, and endocarditis. In these studies, dalbavancin was used as either first-line agent or, more commonly, as consolidation to complete the treatment course and allow for an early discharge [9,13,14]. Data from the dalbavancin clinical trials, where all patients had blood cultures obtained at baseline, indicated that a total of 40 ABSSSI patients who received dalbavancin had bacteremia at baseline caused by one or more of the following organisms: 26 S. aureus (21 MSSA and 5 MRSA), 6 S. agalactiae, 7 S. pyogenes, 2 S. anginosus group, and 1 E. faecalis. Thirty-four of 40 (85.0%) patients who received dalbavancin showed favorable clinical responses at 48 to 72 h and 32/40 (80.0%) were clinical successes at days 26 to 30 [6,15]. Moreover, the efficacy and safety of dalbavancin for the treatment of BSI and cardiovascular infections have been evaluated in many observational studies and case reports [9,14,[16][17][18][19][20].
Gatti et al. recently summarized the results of 144 patients affected by BSI or vascular infection that were treated with dalbavancin. Different dalbavancin dosage treatment durations were administered. Clinical success was obtained in 81.3% of cases and relapse was reported in 3.5% of cases [9]. In a case of prosthetic graft infection due to E. faecium, dalbavancin was successfully administered as a long-term suppressive therapy for a total of 62 weeks [13]. In the DALBA-CEN cohort study, 49 patients affected by BSI that received at least one dose of dalbavancin were assessed. Dalbavancin was administered as a single dose of 1000-1500 mg, or 1000 mg followed by 500 mg at day 8. Clinical success was documented in 100.0% of patients at 90 days (including two cases of BSI caused by E. faecium), with no case of relapse or resistance development [18].
In the present investigation, dalbavancin demonstrated potent in vitro and broad-spectrum activity against Grampositive organisms isolated from patients with BSI in European and US medical centers, with MIC 90 values of 0.03 mg/L for S. aureus, BHS, and VGS; 0.06 mg/L for E. faecalis and S. epidermidis; and 0.12 mg/L for vancomycin-susceptible E. faecium. All organisms, except vancomycin-resistant enterococci and 1 S. haemolyticus isolate, were inhibited at the dalbavancin-susceptible breakpoint of ≤ 0.25 mg/L (US FDA and CLSI criteria). Additionally, dalbavancin MIC values were 8-to 16-fold lower than those of daptomycin and 32-fold lower than those of vancomycin when tested against S. aureus. These results are consistent with in vitro surveillance studies reported since 2002 and cited in several recent reviews. Additionally, these results indicate that resistance to other antimicrobial classes, with the exception of the VanA vancomycin-resistance phenotype, a MIC 50 and MIC 90 values for the US, W-EU, and E-EU collection combined b Trimethoprim-sulfamethoxazole c These breakpoints have been applied to all E. faecalis and E. faecium but are only approved for vancomycin-susceptible E. faecalis d The percentage inhibited at ≤ 0.25 mg/L, the susceptible breakpoint for S. aureus published by US FDA and CLSI e These breakpoints have been applied to all Streptococcus spp. other than S. pneumoniae, but are only approved for S. pyogenes, S. agalactiae, and S. dysgalactiae group f The value in the brackets indicates percentage susceptible dose-dependent (SDD) does not adversely affect dalbavancin activity [4,8,21,22]. These results support further investigations to determine the role of dalbavancin in the treatment of BSI.
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