Update on dalbavancin activity tested against Gram-positive clinical isolates responsible for documented skin and skin-structure infections in US and European hospitals (2011–13)

Sir,

Dalbavancin was approved in the USA (2014) and Europe (2015) for the treatment of adults with acute bacterial skin and skin-structure infections (ABSSSIs) caused by susceptible isolates of Staphylococcus aureus, including MSSA, MRSA, Streptococcus pyogenes, Streptococcus agalactiae and the Streptococcus anginosus group.¹ The ABSSSI indication was based on two identically designed non-inferiority trials comparing dalbavancin safety and efficacy to vancomycin/linezolid.² Results showed that dalbavancin was non-inferior to comparators, and 79.7% (525 of 659) and 79.8% (521 of 653) of patients in the dalbavancin and vancomycin/linezolid arms had an early clinical response indicating treatment success in the pooled analysis, respectively. Moreover, dalbavancin is under consideration for other indications, including paediatric osteomyelitis and community-acquired pneumonia.

A total of 8527 isolates from documented skin and skin-structure infections (SSSIs) were collected from 29 sites in the USA and 39 sites in European (Belgium, Czech Republic, France, Germany, Greece, Hungary, Ireland, Italy, Poland, Portugal, Romania, Slovenia, Spain, Sweden, UK and Ukraine), Israeli, Russian and Turkish regions (herein described as Europe). Isolates were determined clinically significant based on local guidelines and submitted to a central monitoring laboratory (JMI Laboratories, North Liberty, IA, USA), as part of the SENTRY Antimicrobial Surveillance Program (2011–13). Isolates were initially identified by the participating laboratory and identifications confirmed by the monitoring laboratory using standard algorithms and supported by MALDI–TOF–MS (Bruker Daltonics, Bremen, Germany). Broth microdilution susceptibility testing followed the CLSI M07-A10 guidelines.³ Quality assurance was performed by concurrent testing of S. aureus ATCC 29213, Enterococcus faecalis ATCC 29212 and Streptococcus pneumoniae ATCC 49619.⁴ The dalbavancin approved breakpoints for susceptibility were applied: S. aureus, ≤0.12 mg/L; S. anginosus group [also applied for viridans group streptococci (VGS)], ≤0.12 mg/L; S. pyogenes and S. agalactiae, ≤0.12 mg/L [also used for β-haemolytic streptococci and Streptococcus dysgalactiae].^1,5 Breakpoint criteria for comparator agents were those from EUCAST.⁶

Dalbavancin had MIC₅₀ and MIC₉₀ values of 0.06 and 0.06 mg/L for S. aureus from the USA or Europe, irrespective of the methicillin (oxacillin) susceptibility (Table 1). When compared with other agents with similar clinical indications, dalbavancin (MIC_50/90, 0.06/0.06 mg/L) was 4- to 8-fold more potent than daptomycin (MIC_50/90, 0.25/0.5 mg/L) and 16-fold more potent than vancomycin (MIC_50/90, 1/1 mg/L) or linezolid (MIC_50/90, 1/1 mg/L) against MRSA (all 99.7%–100.0% susceptible; Table S1, available as Supplementary data at JAC Online). Clindamycin, gentamicin and tetracycline were more active against MRSA isolates from the USA (80.4%–97.8% susceptible) than Europe (68.4%–83.4% susceptible; Supplementary Data).

MRSA subsets from the USA and Europe displaying vancomycin MICs of 2 mg/L had dalbavancin modal MIC and MIC₅₀ values (0.06 mg/L for both) similar to the populations of S. aureus, MSSA or those MRSA with vancomycin MIC values of ≤1 mg/L; however, the dalbavancin MIC₉₀ increased to 0.12 mg/L (Table 1). Linezolid also demonstrated similar MIC₅₀ values (i.e. 1 mg/L) for MRSA subsets showing a vancomycin MIC of ≤1 or 2 mg/L, while daptomycin tested against the MRSA subset with a vancomycin MIC of 2 mg/L had MIC₅₀ results 2-fold higher than those with an MIC of ≤1 mg/L (Supplementary Data). Of note, gentamicin, tetracycline and trimethoprim/sulfamethoxazole (90.0%–98.3% susceptible) were active against subsets of MRSA from US hospitals, whereas trimethoprim/sulfamethoxazole (98.3%–100.0% susceptible) had antimicrobial coverage against these subsets from Europe.

All VGS (100.0% susceptible) and β-haemolytic streptococci (100.0% susceptible) were susceptible to dalbavancin, which had modal MIC and MIC₅₀ values of ≤0.03 and ≤0.03 mg/L (Table 1). Dalbavancin (MIC₅₀, ≤0.03 mg/L) and penicillin (MIC₅₀, ≤0.06 mg/L) were the most active agents against VGS and S. agalactiae; while dalbavancin (MIC_50/90, ≤0.03/≤0.03 mg/L), penicillin (MIC_50/90, ≤0.06/≤0.06 mg/L) and daptomycin (MIC_50/90, ≤0.06/≤0.06 mg/L) were the most active agents against S. pyogenes (Supplementary Data). Moreover, most agents tested against S. pyogenes demonstrated acceptable (≥90.0% susceptible) antimicrobial coverage, except for erythromycin (88.6%–89.2% susceptible) and tetracycline (71.0%–88.1% susceptible). High susceptibility rates were noted for comparator agents (97.0%–100.0% susceptible) for S. agalactiae, excluding erythromycin, clindamycin and tetracycline (13.6%–83.0% susceptible) (Supplementary Data).

This study provides a contemporary update on the antimicrobial potency and spectrum of dalbavancin and comparator agents tested against key pathogens responsible for SSSIs recovered in the USA and Europe. The results presented herein demonstrate potent activity for dalbavancin, which was consistently greater than comparators, even against S. aureus isolates having decreased susceptibility to vancomycin (i.e. MIC, 2 mg/L). In addition, these results are in agreement with those previously published for Gram-positive surveillance isolates.^7–9 These potent dalbavancin in vitro results along with its pharmacodynamic profile (terminal half-life of 2 weeks) suggest a favourable role for this lipoglycopeptide in the treatment of SSSIs.

Funding

This surveillance study was sponsored by an educational/research grant from Durata Therapeutics (a subsidiary of Actavis plc; Branford, CT, USA) via the SENTRY Antimicrobial Surveillance Program platform. JMI Laboratories also received compensation fees from Durata for services with regards to manuscript preparation. Durata had no involvement in the collection, analysis or interpretation of data.

Transparency declarations

JMI Laboratories received research and educational grants in 2012–14 from: Achaogen, Actelion, Affinium, American Proficiency Institute (API), AmpliPhi Bio, Anacor, Astellas, AstraZeneca, Basilea, BioVersys, Cardeas, Cempra, Cerexa, Cubist, Daiichi, Dipexium, Durata, Fedora, Forest Research Institute, Furiex, Genentech, GlaxoSmithKline, Janssen, Johnson & Johnson, Medpace, Meiji Seika Kaisha, Melinta, Merck, Methylgene, Nabriva, Nanosphere, Novartis, Pfizer, Polyphor, Rempex, Roche, Seachaid, Shionogi, Synthes, The Medicines Co., Theravance, Inc., Theravance Biopharma Antibiotics, Inc., Thermo Fisher, Venatorx, Vertex and Waterloo. Some JMI Laboratories employees are advisors/consultants for Astellas, Cubist, Pfizer, Cempra, Cerexa–Forest and Theravance Biopharma.

Acknowledgements

We wish to thank the following staff members at JMI Laboratories (North Liberty, IA, USA) for technical support: M. Janechek, J. Oberholser, P. Rhomberg, J. Ross, J. Schuchert, J. Streit and L. Woosley.

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