Evaluation of daptomycin combinations with cephalosporins or gentamicin against Streptococcus mitis group strains in an in vitro model of simulated endocardial vegetations (SEVs)

Among the viridans group streptococci, the Streptococcus mitis group is the most common cause of infective endocarditis. These bacteria have a propensity to be ␤-lactam resistant, as well as to rapidly develop high-level and durable resistance to daptomycin (DAP). We compared a parental, daptomycin-susceptible (DAP s ) S. mitis/S. oralis strain and its daptomycin-resistant (DAP r ) variant in a model of experimental endocarditis in terms of (i) their relative fitness in multiple target organs in this model (vegetations, kidneys, spleen) when animals were challenged individually and in a coinfection strategy and (ii) their survivability during therapy with daptomycin-gentamicin (an in vitro combination synergistic against the parental strain). The DAP r variant was initially isolated from the cardiac vegetations of animals with experimental endocarditis caused by the parental DAP s strain following treatment with daptomycin. The parental strain and the DAP r variant were comparably virulent when animals were individually challenged. In contrast, in the coinfection model without daptomycin therapy, at both the 10 6 -and 10 7 -CFU/ml challenge inocula, the parental strain outcompeted the DAP r variant in all target organs, especially the kidneys and spleen. When the animals in the coinfection model of endocarditis were treated with DAP-gentamicin, the DAP s strain was completely eliminated, while the DAP r variant persisted in all target tissues. These data underscore that the acquisition of DAP r in S. mitis/S. oralis does come at an intrinsic fitness cost, although this resistance phenotype is completely protective against therapy with a potentially synergistic DAP regimen.

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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

García-de-la-Mària

Xiong

Pericàs

et al. 2017

“…DAP is a cyclic lipopeptide antibiotic that has been broadly utilized for severe Gram-positive infections, including Staphylococcus aureus and enterococci (11). We have previously demonstrated that combinations of DAP plus ceftaroline (CPT) or ceftriaxone (CRO) are synergistic both in vitro and in the simulated endocardial vegetation (SEV) model against two well-characterized DAP-S S. mitis/oralis parental strains (the penicillin-resistant S. mitis/oralis strain, 351, and the penicillin-susceptible strain S. mitis/oralis SF100) (19). This model has the advantage of being able to precisely simulate human antibiotic concentrations to replicate therapeutic regimens used to treat specific infections (19)(20)(21)(22)(23).…”

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confidence: 99%

Daptomycin Dose-Ranging Evaluation with Single-Dose versus Multidose Ceftriaxone Combinations against Streptococcus mitis /oralis in an Ex Vivo Simulated Endocarditis Vegetation Model

Kebriaei

Rice

Stamper

et al. 2019

Self Cite

The viridans group streptococci (VGS) are a heterogeneous group of organisms which are important components of the normal human oral flora. Among the VGS, the Streptococcus mitis/oralis subgroup is one of the most common causes of infective endocarditis (IE). Daptomycin (DAP) is a potential alternative therapeutic option for invasive S. mitis infections, given high rates of β-lactam resistance and vancomycin tolerance in such strains. However, the ability of these strains to rapidly evolve high-level and durable DAP resistance (DAP-R) is problematic. Recent data suggest that combination DAP-β-lactam therapy circumvents this issue. Human-simulated dose-escalating DAP-alone dose regimens (6, 8, 10, or 12 mg/kg/day times 4 days) versus DAP (6 mg/kg/day) plus ceftriaxone (CRO) (2 g once daily times 4 days or 0.5 g, single dose) were assessed against two prototypical DAP-susceptible (DAP-S) S. mitis/oralis strains (SF100 and 351), as measured by a pharmacokinetic/pharmacodynamic (PK/PD) model of simulated endocardial vegetations (SEVs). No DAP-alone regimen was effective, with regrowth of high-level DAP-R isolates observed for both strains over 96-h exposures. Combinations of DAP-CRO with either single- or multidose regimens yielded significant reductions in log10 CFU/g amounts within SEVs for both strains (∼6 log10 CFU/g) within 24 h. In addition, no DAP-R strains were detected in either DAP-CRO combination regimens over the 96-h exposure. In contrast to prior in vitro studies, no perturbations in two key cardiolipin biosynthetic genes (cdsA and pgsA) were identified in DAP-R SEV isolates emerging from strain 351, despite defective phospholipid production. The combination of DAP-CRO warrants further investigation for treatment of IE due to S. mitis/oralis.

“…However, following exposure to daptomycin in monotherapy, rapid development of HLDR occurs in at least 25% of S. mitis group strains in vitro; this phenomenon was replicated in vivo in EE (15). Of interest, recent investigations utilizing either the rabbit IE model or an ex vivo model featuring simulated endocardial vegetations suggest that daptomycin plus gentamicin (15) or daptomycin plus advanced-generation cephalosporins (ceftriaxone or ceftaroline) (17), respectively, can circumvent emergence of HLDR in VGS strains; however, clinical data for such combinations are lacking. We found that daptomycin plus ampicillin was synergistic in time-kill curves against both tested strains; however, HLDR was detected twice in SPAR-8497 residual after this exposure.…”

Section: Discussionmentioning

confidence: 99%

Endocarditis Caused by Highly Penicillin-Resistant Viridans Group Streptococci: Still Room for Vancomycin-Based Regimens

Pericàs

Nathavitharana

García-de-la-Mària

et al. 2019

Self Cite

Optimal treatment options remain unknown for infective endocarditis (IE) caused by penicillin-resistant (PEN-R) viridans group streptococcal (VGS) strains. The aims of this study were to report two cases of highly PEN-R VGS IE, perform a literature review, and evaluate various antibiotic combinations in vitro and in vivo. The following combinations were tested by time-kill studies and in the rabbit experimental endocarditis (EE) model: PEN-gentamicin, ceftriaxonegentamicin, vancomycin-gentamicin, daptomycin-gentamicin, and daptomycinampicillin. Case 1 was caused by Streptococcus parasanguinis (PEN MIC, 4 g/ml) and was treated with vancomycin plus cardiac surgery. Case 2 was caused by Streptococcus mitis (PEN MIC, 8 g/ml) and was treated with 4 weeks of vancomycin plus gentamicin, followed by 2 weeks of vancomycin alone. Both patients were alive and relapse-free after Ն6 months follow-up. For the in vitro studies, except for daptomycin-ampicillin, all combinations demonstrated both synergy and bactericidal activity against the S. parasanguinis isolate. Only PEN-gentamicin, daptomycin-gentamicin, and daptomycin-ampicillin demonstrated both synergy and bactericidal activity against the S. mitis strain. Both strains developed high-level daptomycin resistance (HLDR) during daptomycin in vitro passage. In the EE studies, PEN alone failed to clear S. mitis from vegetations, while ceftriaxone and vancomycin were significantly more effective (P Ͻ 0.001). The combination of gentamicin with PEN or vancomycin increased bacterial eradication compared to that with the respective monotherapies. In summary, two patients with highly PEN-R VGS IE were cured using vancomycin-based therapy. In vivo, regimens of gentamicin plus either ␤-lactams or vancomycin were more active than their respective monotherapies. Further clinical studies are needed to confirm the role of vancomycin-based regimens for highly PEN-R VGS IE. The emergence of HLDR among these strains warrants caution in the use of daptomycin therapy for VGS IE.KEYWORDS animal models, combination therapy, high-level penicillin resistance, in vitro, infective endocarditis, viridans group streptococci V iridans group streptococci (VGS) are the second most common agent of infective endocarditis (IE) worldwide (1, 2) and remain the most common cause of IE in developing countries (3). Although the overall incidence of VGS IE has declined during