Antimicrobial activity of dalbavancin tested against Gram-positive organisms isolated from patients with infective endocarditis in US and European medical centres Free

Abstract

Background

The management of endocarditis requires aggressive and prolonged antimicrobial treatment. We evaluated the in vitro activity of dalbavancin against bacteria from patients with infective endocarditis.

Methods

A total of 626 Gram-positive organisms were collected from patients with a diagnosis of bacterial endocarditis in the USA (n = 222) and Europe (n = 404) from 2007 to 2017 via the SENTRY Antimicrobial Surveillance Program and were tested for susceptibility to dalbavancin and comparators by broth microdilution.

Results

The most common organisms were Staphylococcus aureus (48.4%), Enterococcus faecalis (19.6%) and viridans group streptococci (VGS; 12.5%). Dalbavancin and daptomycin showed complete activity (100.0% susceptibility per CLSI criteria) against S. aureus, but dalbavancin MIC values were 4- to 8-fold lower. Vancomycin, linezolid and teicoplanin were also active against all S. aureus when CLSI criteria were applied. Ceftaroline was active against all MSSA (MIC₉₀ 0.25 mg/L) and 78.4% of MRSA isolates at ≤1 mg/L. All E. faecalis isolates were susceptible to ampicillin, daptomycin and linezolid, whereas 97.6% of isolates were susceptible to dalbavancin (MIC₉₀ 0.06 mg/L) and 96.7% were susceptible to vancomycin (MIC₉₀ 2 mg/L). All VGS and CoNS isolates were susceptible to dalbavancin, daptomycin, vancomycin and linezolid. Against Enterococcus faecium, 65.7% of isolates were inhibited by ≤0.25 mg/L dalbavancin and 62.9% were vancomycin susceptible.

Conclusions

Dalbavancin exhibited potent in vitro activity against a large collection of Gram-positive isolates recovered from patients with endocarditis in US and European medical centres. These results support further investigations to determine the role of dalbavancin in the treatment of infective endocarditis.

Introduction

Despite improvements in its management, infective endocarditis (IE) remains associated with a mortality rate of ∼20% within the first 30 days and severe complications. Moreover, the spectrum of patients with IE has changed markedly due to the growing number of patients who need prolonged vascular access and patients with implanted intracardiac devices, prosthetic valves and/or other prosthetic material. The number of patients with other risk factors, such as intravenous drug use, has also increased recently.¹

Managing IE requires an aggressive and prolonged treatment approach with specific antimicrobial treatment or a combination of effective antimicrobial agents and surgery to control the infectious source. The antimicrobial agent and duration of therapy are selected with the goal of eradicating the organism from all infection sites. Prolonged combination therapy is often required due to the density of bacteria within vegetations and the slow bactericidal activity of the antimicrobial agents.^2,3

Dalbavancin belongs to the lipoglycopeptide class of antimicrobial agents that act by interrupting bacterial cell wall synthesis resulting in bacterial death.⁴ Dalbavancin was approved in the USA (2014) and Europe (2015) to treat adults with acute bacterial skin and skin structure infections (ABSSSIs) caused by susceptible isolates of Staphylococcus aureus, including MRSA and MSSA, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus anginosus group and vancomycin-susceptible Enterococcus faecalis.^5,6 Dalbavancin allows for very convenient parenteral administration, which can be a single dose of 1500 mg or a dose of 1000 mg followed by 500 mg a week later for treating ABSSSI.^5,6 Dalbavancin is not licensed to treat patients with bloodstream infections or IE, but is potentially important in treating infections due to highly resistant Gram-positive cocci (GPC).^7–9

During preclinical development, dalbavancin has demonstrated potent in vitro activity against S. aureus (including MRSA), streptococci and vancomycin-susceptible enterococci.^4,10,In vitro activity has also been demonstrated against hVISA (MIC range 0.12–0.5 mg/L), VISA (MIC range 0.5–2 mg/L) and other Gram-positive isolates less often recovered from human clinical specimens.^4,7,11 We evaluated dalbavancin’s in vitro activity and potency when tested against a large collection of GPC isolates responsible for IE.

Materials and methods

Bacterial isolates

Between January 2007 and December 2017, the SENTRY Antimicrobial Surveillance Program collected 93 318 bacterial isolates from patients with bloodstream infections in 95 medical centres located in North America, Europe and the Mediterranean region. The isolates were collected consecutively and only one isolate per infection episode was included in the SENTRY Program. Among those 93 318 isolates, a total of 626 Gram-positive organisms were recovered from patients with a diagnosis of bacterial endocarditis and were included in this investigation. The collection included 303 S. aureus, 158 Enterococcus spp. (123 E. faecalis and 35 Enterococcus faecium), 78 viridans group streptococci (VGS), 46 CoNS, 24 β-haemolytic streptococci (BHS), 15 Streptococcus pneumoniae and 2 isolates from other streptococcal species/groups. The 626 isolates were collected from the USA (n = 222; 20 medical centres) and Europe and the Mediterranean region (n = 404; 37 medical centres in 17 countries) and some of these isolates have been included in other dalbavancin susceptibility studies. Isolates were determined to be clinically significant based on local guidelines and submitted to a central monitoring laboratory (JMI Laboratories, North Liberty, IA, USA). Each participating laboratory initially identified isolates, which were confirmed by the reference monitoring laboratory through standard algorithms and supported by MALDI-TOF MS (Bruker Daltonik, Bremen, Germany).

Antimicrobial susceptibility testing

Isolates were susceptibility tested by broth microdilution at JMI Laboratories following guidelines in the CLSI M07 document¹² and by using reference 96-well panels manufactured by JMI Laboratories (2015–17) or acquired from Thermo Fisher (Cleveland, OH, USA; 2007–14). All isolates were tested at JMI Laboratories and 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 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)¹³ and EUCAST (≤0.125 mg/L)¹⁴ were applied. CLSI¹³ and EUCAST¹⁴ breakpoint criteria were used for comparator agents.

Results and discussion

S. aureus (48.4%) was the most common pathogen associated with IE, followed by E. faecalis (19.6%), VGS (12.5%), CoNS (7.3%) and E. faecium (5.6%; Figure S1, available as Supplementary data at JAC Online). Dalbavancin (MIC₅₀ and MIC₉₀ 0.06 mg/L) and daptomycin (MIC_50/90 0.25/0.5 mg/L) showed complete activity (100.0% susceptibility) against S. aureus when CLSI criteria were applied, whereas one isolate was categorized as non-susceptible to dalbavancin (MIC, 0.25 mg/L) per EUCAST criteria (Table 1). Moreover, dalbavancin MIC values were 4- to 8-fold lower than those of daptomycin (Table 2). Linezolid (MIC_50/90 1/2 mg/L), vancomycin (MIC₅₀ and MIC₉₀ 1 mg/L) and teicoplanin (MIC₅₀ and MIC₉₀ ≤2 mg/L) were also active against all S. aureus isolates when CLSI criteria were applied (Table 2). Ceftaroline exhibited potent activity against MSSA (MIC₅₀ and MIC₉₀ 0.25 mg/L; 100.0% susceptibility) and inhibited 78.4% of MRSA isolates (MIC_50/90, 1/2 mg/L) at ≤1 mg/L with the highest MIC value of 2 mg/L (0.0% resistance; Table 2).

All E. faecalis isolates were susceptible to ampicillin (MIC_50/90 ≤1/2 mg/L), daptomycin (MIC_50/90 1/2 mg/L) and linezolid (MIC_50/90 1/2 mg/L), whereas 97.6% (120/123) of isolates were susceptible to dalbavancin (MIC₅₀ and MIC₉₀ 0.06 mg/L) and 96.7% of isolates were susceptible to vancomycin (MIC_50/90 1/2 mg/L; Table 2). Against E. faecalis, dalbavancin MIC values (MIC₅₀ and MIC₉₀ 0.06 mg/L) were 16- to 32-fold lower than those of daptomycin and vancomycin (MIC_50/90 1/2 mg/L for both compounds; Table 2). Among vancomycin-susceptible E. faecalis (n = 119; MIC_50/90 ≤0.03/0.06 mg/L), the highest dalbavancin MIC value was 0.12 mg/L.

All VGS and CoNS isolates were susceptible to dalbavancin, daptomycin, vancomycin and linezolid (Table 2) and the highest ceftaroline MIC values were 0.5 mg/L for VGS and 4 mg/L for CoNS (93.5% inhibited by ≤1 mg/L; data not shown). Against E. faecium, 65.7% of isolates were inhibited by ≤0.25 mg/L dalbavancin and susceptibility to vancomycin (MIC_50/90 1/>16 mg/L) and teicoplanin (MIC_50/90 ≤2/>16 mg/L) was 62.9% and 65.7%, respectively, when CLSI criteria were applied (Tables 1 and 2). All vancomycin-susceptible E. faecium isolates (n = 22) were inhibited by ≤0.25 mg/L dalbavancin (MIC_50/90 0.06/0.12 mg/L). All E. faecium isolates were susceptible to daptomycin (MIC₅₀ and MIC₉₀ 2 mg/L) and linezolid (MIC_50/90 1/2 mg/L; Table 2). Moreover, BHS isolates were susceptible to most antimicrobial agents and only 66.7% (10/15) of S. pneumoniae isolates were susceptible to penicillin at ≤0.06 mg/L (data not shown).

Dalbavancin demonstrated potent in vitro and broad-spectrum activity against Gram-positive organisms isolated from patients with IE in US and European medical centres, with MIC₉₀ values of: 0.06 mg/L for S. aureus, E. faecalis, BHS and VGS; ≤0.03 mg/L for S. pneumoniae; and 0.12 mg/L for vancomycin-susceptible E. faecium and CoNS. Moreover, dalbavancin MIC values were 4- to 8-fold lower than those of daptomycin and 16-fold lower than those of vancomycin when tested against S. aureus. To our knowledge, these results are the first for dalbavancin against IE isolates; they are consistent with in vitro surveillance studies reported since 2002 and cited in several recent reviews.^4,10,11 Furthermore, resistance to other antimicrobial classes, with the exception of the VanA vancomycin-resistance phenotype, does not adversely affect dalbavancin activity.⁷

Dalbavancin’s high protein binding and prolonged t_½ allow for easily and consistently attainable therapeutic levels. The free serum drug levels are adequate to provide excellent tissue penetration and several clinical trials have demonstrated its tolerability, efficacy and non-inferiority compared with standard therapy.^4,5,15 The results of this investigation corroborate and expand published data on the in vitro activity of dalbavancin. These in vitro results, prolonged t_½ and convenient administration support further investigations to determine the role of dalbavancin in the treatment of IE.

Acknowledgements

We would like to thank all participants of the International Dalbavancin Evaluation of Activity (IDEA) and the SENTRY Programs (for providing bacterial isolates) and the following staff members at JMI Laboratories: L. Flanigan, J. Oberholser, J. E. Schuchert and J. M. Streit (for technical support and/or assistance with manuscript preparation).

Funding

This study was supported by Allergan. Allergan was involved in the design and decision to present these results and JMI Laboratories received compensation fees for services related to preparing this manuscript. Allergan had no involvement in the collection, analysis and interpretation of data.

Transparency declarations

JMI Laboratories was contracted to perform services in 2017 and 2018 for Achaogen, Allecra Therapeutics, Allergan, Amplyx Pharmaceuticals, Antabio, API, Astellas Pharma, AstraZeneca, Athelas, Basilea Pharmaceutica, Bayer AG, Becton, Dickinson and Co., Boston Pharmaceuticals, CEM-102 Pharma, Cempra, Cidara Therapeutics, Inc., CorMedix, CSA Biotech, Cutanea Life Sciences, Inc., Entasis Therapeutics, Inc., Geom Therapeutics, Inc., GSK, Iterum Pharma, Medpace, Melinta Therapeutics, Inc., Merck & Co., Inc., MicuRx Pharmaceuticals, Inc., N8 Medical, Inc., Nabriva Therapeutics, Inc., NAEJA-RGM, Novartis, Paratek Pharmaceuticals, Inc., Pfizer, Polyphor, Ra Pharma, Rempex, Riptide Bioscience Inc., Roche, Scynexis, Shionogi, Sinsa Labs Inc., Skyline Antiinfectives, Sonoran Biosciences, Spero Therapeutics, Symbiotica, Synlogic, Synthes Biomaterials, TenNor Therapeutics, Tetraphase, The Medicines Company, Theravance Biopharma, VenatoRx Pharmaceuticals, Inc., Wockhardt, Yukon Pharma, Zai Laboratory and Zavante Therapeutics, Inc. There are no speakers’ bureaus or stock options to declare.

References