Antimicrobial Susceptibility Studies
Surrogate analysis of vancomycin to predict susceptible categorization of dalbavancin

https://doi.org/10.1016/j.diagmicrobio.2015.01.017Get rights and content

Highlights

  • A collection of 64,815 strains reference MIC tested against dalbavancin and vancomycin were utilized for surrogate analysis.

  • Concordant categorical agreement for vancomycin susceptibility to predict dalbavancin susceptibility (≤0.12 μg/mL) was 97.7–100.0%.

  • Due to lack of available diagnostic reagents, dalbavancin activity can be inferred by vancomycin results for S. aureus and other Food and Drug Administration–indicated species.

Abstract

Dalbavancin (DAL) represents a recently approved addition for the treatment of acute bacterial skin and skin structure infections (ABSSSIs). Newly released antimicrobial agents are rarely found on commercial susceptibility testing devices, and surrogate testing may be an option for clinical microbiology laboratories. A total of 33,688 Staphylococcus aureus, 2800 viridans group streptococci (VGS), and 5722 β-hemolytic streptococci (BHS) were included in this cross-susceptibility (DAL versus vancomycin [VAN]) analysis as well as 4576 coagulase-negative staphylococci and 6515 enterococci (nonindicated species groups). Isolates were collected as part of the SENTRY Antimicrobial Surveillance Program for the United States (USA) and Europe (2011–2013). Susceptibility testing followed CLSI (M07-A9 and M100-S24) methods. USA Food and Drug Administration (DAL) and CLSI (VAN) breakpoint criteria were used for correlations between DAL and VAN susceptibility results. A categorical agreement (CA; susceptible) rate of 99.9% was observed between DAL and VAN when testing S. aureus. Only 48 (0.14%) very major (false-susceptible) errors were noted against VAN-susceptible isolates that displayed a DAL-nonsusceptible (MIC, 0.25 or 0.5 μg/mL) phenotype. When susceptible MIC correlations were analyzed against indicated BHS species (Streptococcus agalactiae and Streptococcus pyogenes), an overall CA rate of 97.7–100.0% was obtained. Complete (100.0%) CA was documented for S. pyogenes, as well as against all VGS isolates, including the indicated Streptococcus anginosus group (758 strains). In conclusion, high susceptible CA rates between DAL and VAN were observed when testing a contemporary collection of indicated clinical isolates found in ABSSSI. VAN-susceptible isolates can be inferred to be inhibited by DAL (97.7–100.0%) at the regulatory agency–approved susceptible interpretive breakpoint of ≤0.12 μg/mL.

Introduction

Dalbavancin is a recently approved lipoglycopeptide agent for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) in adults, known or suspected to be caused by designated susceptible strains of Gram-positive pathogens (Billeter et al., 2008, Boucher et al., 2014, Chambers, 2014, Dalvance™, 2014, Jones et al., 2005, Streit et al., 2004, Zhanel et al., 2010). Pharmacokinetic/pharmacodynamic characteristics of dalbavancin (terminal half-life of 2 weeks, 93% protein binding) allow for a 2 intravenous dose regimen of 1000 mg followed 1 week later by 500 mg (Andes and Craig, 2007, Chambers, 2014, Dorr et al., 2005). Two ABSSSI trials (DISCOVER 1 and DISCOVER 2) comparing dalbavancin to a control regimen of vancomycin/linezolid showed that dalbavancin was noninferior to the comparators leading to approval by the USA Food and Drug Administration (USA-FDA) (Boucher et al., 2014) and confirming conclusions from earlier clinical trials (Jauregui et al., 2005, Seltzer et al., 2003).

Lipoglycopeptides (dalbavancin, oritavancin, and telavancin) have physiochemical features that can challenge the development of in vitro methods for susceptibility testing (Rennie et al., 2007, Zhanel et al., 2010). Early studies, particularly with dalbavancin, demonstrated that reference MIC (agar dilution and broth microdilution) and agar diffusion (disk tests) methods were flawed by high binding affinities of these drugs for media components and plastics as well as limited diffusion in agar due to the drug's high molecular size (Rennie et al., 2007). A reference broth microdilution method for all marketed lipoglycopeptides has been approved and published by the Clinical and Laboratory Standards Institute (CLSI) wherein a surfactant (polysorbate 80 at 0.002%) supplement was added to the Mueller–Hinton broth to minimize binding to the plastic trays and thus accurately measuring drug potency (Clinical and Laboratory Standards Institute (CLSI), 2012, Clinical and Laboratory Standards Institute (CLSI), 2014). Dalbavancin, among the clinically approved lipoglycopeptides, has been studied in resistance surveillance trials for over a decade (Biedenbach et al., 2009, Jones et al., 2005, Streit et al., 2004) and has a validated E-test (Fritsche et al., 2006) and a dry-form broth microdilution method (Jones et al., 2004), plus published quality control (QC) guidelines (Anderegg et al., 2003, Clinical and Laboratory Standards Institute (CLSI), 2014) to assure precise measures of it's activity.

However, like other newer antimicrobial agents at the time of USA-FDA approval (Jones et al., 2013b), commercial diagnostic devices for dalbavancin may not be available. In the interim, 1 possible strategy for dalbavancin in vitro testing would be to apply the results of a commonly tested chemically similar agent such as vancomycin for a surrogate marker of susceptibility (Clinical and Laboratory Standards Institute (CLSI), 2014, Jones and Pfaller, 2001, Jones et al., 2007). This type of analysis (cross-susceptibility) was initially reported for dalbavancin in 2006 (Jones et al., 2006) and showed diagnostic promise but did not use the recent regulatory-approved interpretive breakpoint criteria for this new agent (Dalvance™, 2014). We present here, an updated analysis of year 2011–2013 clinical strains of Gram-positive pathogens to establish vancomycin susceptibility results as a possible surrogate predictor of dalbavancin activity.

Section snippets

Organisms tested

Major Gram-positive pathogens collected by the SENTRY Antimicrobial Surveillance Program (64,815 strains) during 2011–2013 were used in this surrogate testing analysis. These organisms from USA and European medical centers included Staphylococcus aureus (33,688), coagulase-negative staphylococci (CoNS; 4576, including 5 major species with >200 isolates); enterococci (6515; mostly Enterococcus faecalis at 4126 isolates), β-hemolytic streptococci (5722, including 5 species or serogroups with >200

Results and discussion

Table 1 presents the most recent published spectrum and activity of dalbavancin tested in a resistance surveillance study (SENTRY Program, 2011–2012) for a collection of 3144 isolates of Gram-positive pathogens (Jones et al., 2013a, Jones et al., 2013c). Dalbavancin exhibits high potencies (MIC90, ≤0.06 μg/mL) for all tabulated species except S. agalactiae and the enterococci, and all MIC values were ≤0.25 μg/mL, except for 41.6% of Enterococcus spp. (vancomycin-resistant enterococci [VRE]

Acknowledgments

The research and publication process was supported by Durata Therapeutics.

JMI Laboratories has received research and educational grants in 2012–2014 from Achaogen, Actelion, Affinium, American Proficiency Institute, 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,

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