scholarly journals Strain-Specific Adaptations of Streptococcus mitis-oralis to Serial In Vitro Passage in Daptomycin (DAP): Genotypic and Phenotypic Characteristics

Antibiotics ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 520
Author(s):  
Nagendra N. Mishra ◽  
Truc T. Tran ◽  
Cesar A. Arias ◽  
Ravin Seepersaud ◽  
Paul M. Sullam ◽  
...  
Keyword(s):  
Surface Charge ◽  
Membrane Fluidity ◽  
Nucleotide Polymorphisms ◽  
Membrane Phospholipids ◽  
Streptococcus Mitis ◽  
Positive Surface Charge ◽  
Identical Manner ◽  
High Level ◽  
Viridans Group Streptococci

Viridans group streptococci (VGS), especially the Streptococcus mitis-oralis subgroup, are pivotal pathogens in a variety of invasive endovascular infections, including “toxic shock” in neutropenic cancer patients and infective endocarditis (IE). Previously, we showed that the serial in vitro passage of S. mitis-oralis strains in sublethal daptomycin (DAP) resulted in rapid, high-level and stable DAP-resistance (DAP-R), which is accompanied by distinct changes in several genotypic and phenotypic signatures: (1) the disappearance of two key membrane phospholipids, phosphatidylglycerol (PG) and cardiolipin (CL); (2) increased membrane fluidity; (3) increased positive surface charge; (4) single nucleotide polymorphisms (SNPs) in two loci involved in CL biosynthesis (pgsA; cdsA); and (5) DAP hyperaccumulation. The current study examined these same metrics following in vitro serial DAP passages of a separate well-characterized S. mitis-oralis bloodstream isolate (SF100). Although some metrics seen in prior DAP post-passage strains were recapitulated with SF100 (e.g., pgsA SNPs, enhanced membrane fluidity), we observed the following major differences (comparing the parental versus post-passage variant): (1) no change in PG content; (2) reduced, but not absent, CL, with enhancement in phosphatidic acid (PA) content; (3) an unusual pattern of CL localization; (4) significantly decreased positive surface charge; (5) no difference in DAP accumulation; and (6) no cdsA SNPs. Thus, S. mitis-oralis strains are not “pre-programmed” phenotypically and/or genotypically to adapt in an identical manner during the evolution of the DAP-R.

scholarly journals Mutations in cdsA and pgsA Correlate with Daptomycin Resistance in Streptococcus mitis and S. oralis

2018 ◽  
Vol 63 (2) ◽  
pp. e01531-18 ◽  
Author(s):  
Truc T. Tran ◽  
Nagendra N. Mishra ◽  
Ravin Seepersaud ◽  
Lorena Diaz ◽  
Rafael Rios ◽  
...  
Keyword(s):  
Cell Membrane ◽  
Cell Membranes ◽  
Complete Disappearance ◽  
Biosynthesis Pathway ◽  
Streptococcus Mitis ◽  
Content Type ◽  
High Level ◽  
Viridans Group Streptococci

ABSTRACT We investigated the ability of several recent clinical viridans group streptococci (VGS) bloodstream isolates (Streptococcus mitis/S. oralis subgroup) from daptomycin (DAP)-naive patients to develop DAP resistance in vitro. All strains rapidly developed high-level and stable DAP resistance. Substitutions in two enzymes involved in the cardiolipin biosynthesis pathway were identified, i.e., CdsA (phosphatidate cytidylyltransferase) and PgsA (CDP-diacylglycerol-glycerol-3-phosphate-3-phosphatidyltransferase). These mutations were associated with complete disappearance of phosphatidylglycerol and cardiolipin from cell membranes. DAP interactions with the cell membrane differed in isolates with PgsA versus CdsA substitutions.

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

2019 ◽  
Vol 63 (6) ◽  
Author(s):  
Razieh Kebriaei ◽  
Seth A. Rice ◽  
Kyle C. Stamper ◽  
Ravin Seepersaud ◽  
Cristina Garcia-de-la-Maria ◽  
...  
Keyword(s):  
Single Dose ◽  
Ex Vivo ◽  
Therapeutic Option ◽  
Streptococcus Mitis ◽  
Oral Flora ◽  
Content Type ◽  
High Level ◽  
Viridans Group Streptococci ◽  
Combination Regimens

ABSTRACT 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.

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

2017 ◽  
Vol 61 (5) ◽  
Author(s):  
C. Garcia-de-la-Maria ◽  
Y. Q. Xiong ◽  
J. M. Pericas ◽  
Y. Armero ◽  
A. Moreno ◽  
...  
Keyword(s):  
Infective Endocarditis ◽  
Parental Strain ◽  
Durable Resistance ◽  
Relative Fitness ◽  
Streptococcus Mitis ◽  
Content Type ◽  
Target Organs ◽  
High Level ◽  
Viridans Group Streptococci

ABSTRACT Among the viridans group streptococci, the Streptococcus mitis group is the most common cause of infective endocarditis. These bacteria have a propensity to be β-lactam resistant, as well as to rapidly develop high-level and durable resistance to daptomycin (DAP). We compared a parental, daptomycin-susceptible (DAPs) S. mitis/S. oralis strain and its daptomycin-resistant (DAPr) 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 DAPr variant was initially isolated from the cardiac vegetations of animals with experimental endocarditis caused by the parental DAPs strain following treatment with daptomycin. The parental strain and the DAPr variant were comparably virulent when animals were individually challenged. In contrast, in the coinfection model without daptomycin therapy, at both the 106- and 107-CFU/ml challenge inocula, the parental strain outcompeted the DAPr 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 DAPs strain was completely eliminated, while the DAPr variant persisted in all target tissues. These data underscore that the acquisition of DAPr 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.

scholarly journals In Vitro Activities of Fluoroquinolones against Antibiotic-Resistant Blood Culture Isolates of Viridans Group Streptococci from across Canada

1999 ◽  
Vol 43 (9) ◽  
pp. 2299-2301 ◽  
Author(s):  
J. C. S. de Azavedo ◽  
L. Trpeski ◽  
S. Pong-Porter ◽  
S. Matsumura ◽  
D. E. Low
Keyword(s):  
Blood Culture ◽  
Streptococcus Mitis ◽  
Antibiotic Resistant ◽  
Streptococcus Sanguis ◽  
Viridans Group Streptococci

ABSTRACT Among 418 blood culture isolates of viridans group streptococci obtained between 1995 and 1997, the in vitro rates of nonsusceptibility to penicillin, erythromycin, tetracycline, and trimethoprim-sulfamethoxazole were 28, 29, 24, and 14%, respectively. The most prevalent group (125 strains) was Streptococcus mitis, followed by Streptococcus sanguis (56 strains). For 236 (56%) strains resistant to one or more antibiotics, the ciprofloxacin MIC at which 90% of the isolates were inhibited (MIC90) was 4 μg/ml, whereas the MIC90s of trovafloxacin, grepafloxacin, and gatifloxacin were 0.25 μg/ml.

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

2019 ◽  
Vol 63 (8) ◽  
Author(s):  
Juan M. Pericàs ◽  
Ruvandhi Nathavitharana ◽  
Cristina Garcia-de-la-Mària ◽  
Carles Falces ◽  
Juan Ambrosioni ◽  
...  
Keyword(s):  
Bactericidal Activity ◽  
Treatment Options ◽  
Content Type ◽  
High Level ◽  
Viridans Group Streptococci ◽  
Time Kill

ABSTRACT 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, ceftriaxone-gentamicin, vancomycin-gentamicin, daptomycin-gentamicin, and daptomycin-ampicillin. Case 1 was caused by Streptococcus parasanguinis (PEN MIC, 4 μg/ml) and was treated with vancomycin plus cardiac surgery. Case 2 was caused by Streptococcus mitis (PEN MIC, 8 μg/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 ≥6 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 < 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 β-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.

scholarly journals Efficacy of Trovafloxacin in Treatment of Experimental Staphylococcal or Streptococcal Endocarditis

1999 ◽  
Vol 43 (1) ◽  
pp. 77-84 ◽  
Author(s):  
J. M. Entenza ◽  
J. Vouillamoz ◽  
M. P. Glauser ◽  
P. Moreillon
Keyword(s):  
Staphylococcus Aureus ◽  
Oral Dose ◽  
Experimental Model ◽  
Streptococcus Mitis ◽  
Control Drug ◽  
Streptococcus Sanguis ◽  
Viridans Group Streptococci ◽  
Higher Doses

ABSTRACT The efficacy of trovafloxacin against Staphylococcus aureus and viridans group streptococci was investigated in vitro and in an experimental model of endocarditis. The MICs at which trovafloxacin and ciprofloxacin inhibited 90% of clinical isolates of such bacteria (MIC90s) were (i) 0.03 and 2 mg/liter, respectively, for 30 ciprofloxacin-susceptible S. aureus isolates, (ii) 32 and 128 mg/liter, respectively, for 20 ciprofloxacin-resistant S. aureus isolates, and (iii) 0.25 and 8 mg/liter, respectively, for 28 viridans group streptococci. Rats with aortic vegetations were infected with either of two ciprofloxacin-susceptible but methicillin-resistant S. aureus strains (strains COL and P8), one penicillin-susceptibleStreptococcus sanguis strain, or one penicillin-resistantStreptococcus mitis strain. Rats were treated for 3 or 5 days with doses that resulted in kinetics that simulated those achieved in humans with trovafloxacin (200 mg orally once a day), ciprofloxacin (750 mg orally twice a day), vancomycin (1 g intravenously twice a day), or ceftriaxone (2 g intravenously once a day). Against the staphylococci, the activities of both trovafloxacin and ciprofloxacin were equivalent to that of vancomycin, and treatment of endocarditis with these drugs was successful (P < 0.05). However, ciprofloxacin selected for resistant derivatives in vitro and in vivo, whereas trovafloxacin was 10 to 100 times less prone than ciprofloxacin to select for resistance in vitro and did not select for resistance in vivo. Against the two streptococcal isolates, trovafloxacin significantly (P < 0.05) decreased bacterial counts in the vegetations but was less effective than the control drug, ceftriaxone. Thus, a simulated oral dose of trovafloxacin (200 mg per day) was effective against ciprofloxacin-susceptible staphylococci and was less likely than ciprofloxacin to select for resistance. The simulated oral dose of trovafloxacin also had some activity against streptococcal endocarditis, but optimal treatment of infections caused by such organisms might require higher doses of the drug.

scholarly journals EarlyIn VitroandIn VivoDevelopment of High-Level Daptomycin Resistance Is Common in Mitis Group Streptococci after Exposure to Daptomycin

2013 ◽  
Vol 57 (5) ◽  
pp. 2319-2325 ◽  
Author(s):  
Cristina García-de-la-Mària ◽  
Juan M. Pericas ◽  
Ana del Río ◽  
Ximena Castañeda ◽  
Xavier Vila-Farrés ◽  
...  
Keyword(s):  
Body Weight ◽  
Streptococcus Bovis ◽  
Streptococcus Mitis ◽  
Content Type ◽  
Group 4 ◽  
Viridans Group Streptococcus ◽  
High Level ◽  
Time Kill

ABSTRACTThe development of high-level daptomycin resistance (HLDR; MIC of ≥256 mg/liter) after exposure to daptomycin has recently been reported in viridans group streptococcus (VGS) isolates. Our study objectives were as follows: to know whetherin vitrodevelopment of HLDR after exposure to daptomycin was common among clinical isolates of VGS andStreptococcus bovis; to determine whether HLDR also developed during the administration of daptomycin to treat experimental endocarditis caused by the daptomycin-susceptible, penicillin-resistantStreptococcus mitisstrainS. mitis351; and to establish whether combination with gentamicin prevented the development of HLDRin vitroandin vivo. In vitrostudies were performed with 114 VGS strains (mitis group, 92; anginosus group, 10; mutans group, 8; and salivarius group, 4) and 54Streptococcus bovisstrains isolated from 168 consecutive patients with infective endocarditis diagnosed between 1995 and 2010. HLDR was only observed after 24 h of exposure to daptomycin in 27% of the mitis group, including 27% ofS. mitisisolates, 47% ofS. oralisisolates, and 13% ofS. sanguisisolates. In our experimental model, HLDR was detected in 7/11 (63%) and 8/12 (67%) isolates recovered from vegetations after 48 h of daptomycin administered at 6 mg/kg of body weight/24 h and 10 mg/kg/24 h, respectively.In vitro, time-kill experiments showed that daptomycin plus gentamicin was bactericidal againstS. mitis351 at tested concentrations of 0.5 and 1 times the MIC and prevented the development of HLDR.In vivo, the addition of gentamicin at 1 mg/kg/8 h to both daptomycin arms prevented HLDR in 21 out of 23 (91%) rabbits. Daptomycin plus gentamicin was at least as effective as vancomycin plus gentamicin. In conclusion, HLDR develops rapidly and frequentlyin vitroandin vivoamong mitis group streptococci. Combining daptomycin with gentamicin enhanced its activity and prevented the development of HLDR in most cases.

Prevention of High-Level Daptomycin-Resistance Emergence In Vitro in Streptococcus mitis-oralis by Using Combination Antimicrobial Strategies

2018 ◽  
Vol 75 (8) ◽  
pp. 1062-1067 ◽  
Author(s):  
Brianne Zapata ◽  
Danya N. Alvarez ◽  
Sabrina Farah ◽  
Cristina Garcia-de-la-Maria ◽  
Jose M. Miro ◽  
...  
Keyword(s):  
Streptococcus Mitis ◽  
High Level

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

2017 ◽  
Vol 61 (5) ◽  
Author(s):  
Hannah M. Adams ◽  
Luke R. Joyce ◽  
Ziqiang Guan ◽  
Ronda L. Akins ◽  
Kelli L. Palmer
Keyword(s):  
Drug Exposure ◽  
Essential Gene ◽  
Model Organisms ◽  
Membrane Phospholipids ◽  
Streptococcus Mitis ◽  
Gram Positive ◽  
Content Type ◽  
Anionic Phospholipids ◽  
Resistant Strains ◽  
High Level

ABSTRACT Synthesis and integrity of the cytoplasmic membrane are fundamental to cellular life. Experimental evolution studies have hinted at unique physiology in the Gram-positive bacteria Streptococcus mitis and S. oralis. These organisms commonly cause bacteremia and infectious endocarditis (IE) but are rarely investigated in mechanistic studies of physiology and evolution. Unlike in other Gram-positive pathogens, high-level (MIC ≥ 256 μg/ml) daptomycin resistance rapidly emerges in S. mitis and S. oralis after a single drug exposure. In this study, we found that inactivating mutations in cdsA are associated with high-level daptomycin resistance in S. mitis and S. oralis IE isolates. This is surprising given that cdsA is an essential gene for life in commonly studied model organisms. CdsA is the enzyme responsible for the synthesis of CDP-diacylglycerol, a key intermediate for the biosynthesis of all major phospholipids in prokaryotes and most anionic phospholipids in eukaryotes. Lipidomic analysis by liquid chromatography-mass spectrometry (LC-MS) showed that daptomycin-resistant strains have an accumulation of phosphatidic acid and completely lack phosphatidylglycerol and cardiolipin, two major anionic phospholipids in wild-type strains, confirming the loss of function of CdsA in the daptomycin-resistant strains. To our knowledge, these daptomycin-resistant streptococci represent the first model organisms whose viability is CdsA independent. The distinct membrane compositions resulting from the inactivation of cdsA not only provide novel insights into the mechanisms of daptomycin resistance but also offer unique opportunities to study the physiological functions of major anionic phospholipids in bacteria.

scholarly journals Characterization of High-Level Daptomycin Resistance in Viridans Group Streptococci Developed uponIn VitroExposure to Daptomycin

2015 ◽  
Vol 59 (4) ◽  
pp. 2102-2112 ◽  
Author(s):  
Ronda L. Akins ◽  
Bradley D. Katz ◽  
Catherine Monahan ◽  
Dylan Alexander
Keyword(s):  
Drug Exposure ◽  
Total Drug ◽  
Normal Flora ◽  
Vegetation Model ◽  
Content Type ◽  
Drug Concentrations ◽  
High Level ◽  
Viridans Group Streptococci

ABSTRACTViridans 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 μg/ml) using anin 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 log10CFU was seen for all isolates and dosages except daptomycin at 6 mg/kg, which achieved a reduction of 2.7 log10CFU/g against one strain (Streptococcus gordonii1649) 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 μg/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.

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