Characterization of High-Level Daptomycin Resistance in Viridans Group Streptococci Developed upon In Vitro Exposure to Daptomycin

Abstract

cViridans group streptococci (VGS) are part of the normal flora that may cause bacteremia, often leading to endocarditis. We evaluated daptomycin against four clinical strains of VGS (MICs ‫؍‬ 1 or 2 g/ml) using an in vitro-simulated endocardial vegetation model, a simulated bacteremia model, and kill curves. Daptomycin exposure was simulated at 6 mg/kg of body weight and 8 mg/kg every 24 h for endocardial and bacteremia models. Total drug concentrations were used for analyses containing protein (albumin and pooled human serum), and free (unbound) drug concentrations (93% protein bound) were used for analyses not containing protein. Daptomycin MICs in the presence of protein were significantly higher than those in the absence of protein. Despite MICs below or at the susceptible breakpoint, all daptomycin regimens demonstrated limited kill in both pharmacodynamic models. A reduction of approximately 1 to 2 log 10 CFU was seen for all isolates and dosages except daptomycin at 6 mg/kg, which achieved a reduction of 2.7 log 10 CFU/g against one strain (Streptococcus gordonii 1649) in the endocardial model. Activity was similar in both pharmacodynamic models in the presence or absence of protein. Similar activity was noted in the kill curves over all multiples of the MIC. Regrowth by 24 h was seen even at 8؋ MIC. Postexposure daptomycin MICs for both pharmacodynamic models increased to >256 g/ml for all isolates by 24 and 72 h. Despite susceptibility to daptomycin by standard MIC methods, these VGS developed high-level daptomycin resistance (HLDR) after a short duration following drug exposure not attributed to modification or inactivation of daptomycin. Further evaluation is warranted to determine the mechanism of resistance and clinical implications.

Streptococcus mitis and S. oralis Lack a Requirement for CdsA, the Enzyme Required for Synthesis of Major Membrane Phospholipids in Bacteria

“…mitis and S. oralis purge their membranes of PG and, as previously shown, DAP MICs increase up to 512-fold higher than DAP-sensitive parental strains (17, 18). …”

“…S. oralis 1648 was not analyzed due to its preexisting rifampin resistance (17). Spontaneous DAP resistance arose at an average frequency of 1 × 10 −6 for both strains on 10 μg/ml of DAP and at an average frequency of 7 × 10 −7 for both strains on 128 μg/ml of DAP.…”

“…mitis and S. oralis IE isolates after a single DAP exposure in a simulated endocardial vegetation model (17). High-level DAP resistance after a single drug exposure was also reported by García-de-la-Mària et al (16) for a collection of mitis group VGS.…”

Impact of High-Level Daptomycin Resistance in the Streptococcus mitis Group on Virulence and Survivability during Daptomycin Treatment in Experimental Infective Endocarditis

“…This has raised the notion of using daptomycin (DAP) for the treatment of invasive S. mitis group infections. Recent studies have somewhat dampened the enthusiasm for the latter approach, as many S. mitis group strains have a unique propensity to evolve rapid, durable, and high-level daptomycin resistance (DAP r ) in vitro, ex vivo, and in vivo (17)(18)(19). This study investigated the impact of the acquisition of DAP r upon both the intrinsic fitness and survivability during treatment with DAP of such strains in a model of IE featuring coinfection with a DAP-susceptible (DAP s ) parental S. mitis/S.…”

Prevalence of macrolide–lincosamide resistance and multidrug resistance phenotypes in streptococcal isolates causing infections in European hospitals: Evaluation of the in vitro activity of oritavancin and comparator agents

“…Although VGS are generally susceptible to most anti-Gram-positive agents, resistance has been known to occur against macrolideslincosamides-streptogramin B (MLS B ), penicillin and fluoroquinolones [13]. Moreover, difficult-to-treat nutritionally variant streptococci [14] and occasional reports of daptomycin, linezolid and even vancomycin resistance among VGS isolates have been published [15][16][17].…”