scholarly journals Surotomycin Demonstrates LowIn VitroFrequency of Resistance and Rapid Bactericidal Activity in Clostridium difficile, Enterococcus faecalis, and Enterococcus faecium

2014 ◽  
Vol 58 (7) ◽  
pp. 3976-3982 ◽  
Author(s):  
Carmela T. M. Mascio ◽  
Laurent Chesnel ◽  
Grace Thorne ◽  
Jared A. Silverman
Keyword(s):  
Clostridium Difficile ◽  
Enterococcus Faecalis ◽  
Bactericidal Activity ◽  
Enterococcus Faecium ◽  
Limit Of Detection ◽  
Serial Passage ◽  
Cross Resistance ◽  
Content Type ◽  
Naive Control ◽  
Emergence Of Resistance

ABSTRACTSurotomycin (CB-183,315) is an orally administered, minimally absorbed, selective bactericidal cyclic lipopeptide in phase 3 development for the treatment ofClostridium difficile-associated diarrhea. The aim of this study was to evaluate the emergence of resistance inC. difficile(ATCC 700057 and three recent clinical isolates from the restriction endonuclease analysis groups BI, BK, and K), vancomycin-susceptible (VS)Enterococcus faecalis(ATCC 49452), vancomycin-resistant (VR)E. faecalis(ATCC 700802), VSEnterococcus faecium(ATCC 6569), and VRE. faecium(ATCC 51559) under anaerobic conditions. The rate of spontaneous resistance was below the limit of detection (<10−8to <10−9) for surotomycin at 16 and 32× the MIC for all isolates tested. Under selective pressure by serial passage,C. difficilegrew in a maximum of 4 μg/ml surotomycin (final MICs of 2 to 8 μg/ml [4- to 16-fold higher than those of the naive control]) at day 15, with the exception of theC. difficileBK strain, which grew in 16 to 32 μg/ml (final MICs of 8 to 32 μg/ml [16- to 64-fold higher than those of the naive control]). Enterococci remained relatively unchanged over 15 days, growing in a maximum of 8 μg/ml surotomycin (final MICs of 2 to 16 μg/ml [8- to 64-fold higher than those of the naive control]). Of the isolates tested, no cross-resistance to vancomycin, rifampin, ampicillin, metronidazole, or moxifloxacin was observed. Surotomycin at 20× MIC demonstrated equally rapid bactericidal activity (≥3-log-unit reduction in CFU/ml in ≤8 h) against naive and reduced-susceptibility isolates ofC. difficile, VSEnterococcus(VSE), and VREnterococcus(VRE), except forC. difficileBK (2.6-log-unit reductions for both). These results suggest that emergence of resistance to surotomycin againstC. difficile,E. faecalis, andE. faeciumis likely to be rare.

scholarly journals Oritavancin Activity Tested against Molecularly Characterized Staphylococci and Enterococci Displaying Elevated Linezolid MIC Results

2016 ◽  
Vol 60 (6) ◽  
pp. 3817-3820
Author(s):  
Rodrigo E. Mendes ◽  
David J. Farrell ◽  
Helio S. Sader ◽  
Robert K. Flamm ◽  
Ronald N. Jones
Keyword(s):  
Enterococcus Faecalis ◽  
Enterococcus Faecium ◽  
Cross Resistance ◽  
Content Type

Oritavancin (MIC50/90, 0.03/0.06 to 0.12 μg/ml) had potent activity against linezolid-resistant staphylococci, as well asEnterococcus faecalisandEnterococcus faecium(oritavancin MIC50/90, 0.015/0.12 μg/ml against both species). All linezolid-resistant isolates were inhibited by oritavancin at ≤0.12 μg/ml. These results confirmed the absence of cross-resistance between linezolid and oritavancin in staphylococci and enterococci.

scholarly journals In VitroandIn VivoCharacterization of CB-183,315, a Novel Lipopeptide Antibiotic for Treatment of Clostridium difficile

2012 ◽  
Vol 56 (10) ◽  
pp. 5023-5030 ◽  
Author(s):  
Carmela T. M. Mascio ◽  
Lawrence I. Mortin ◽  
Karen T. Howland ◽  
Andrew D. G. Van Praagh ◽  
Shuxin Zhang ◽  
...  
Keyword(s):  
Clostridium Difficile ◽  
Limit Of Detection ◽  
Disease Onset ◽  
Serial Passage ◽  
Postantibiotic Effect ◽  
Hamster Model ◽  
Content Type ◽  
Lipopeptide Antibiotic ◽  
Time Kill

ABSTRACTCB-183,315 is a novel lipopeptide antibiotic structurally related to daptomycin currently in phase 3 clinical development forClostridium difficile-associated diarrhea (CDAD). We report here thein vitromechanism of action, spontaneous resistance incidence, resistance by serial passage, time-kill kinetics, postantibiotic effect, and efficacy of CB-183,315 in a hamster model of lethal infection.In vitrodata showed that CB-183,315 dissipated the membrane potential ofStaphylococcus aureuswithout inducing changes in membrane permeability to small molecules. The rate of spontaneous resistance to CB-183,315 at 8× the MIC was below the limit of detection inC. difficile. Under selective pressure by serial passage with CB-183,315 againstC. difficile, the susceptibility of the bacteria changed no more than 2-fold during 15 days of serial passages. At 16× the MIC, CB-183,315 produced a ≥3-log reduction ofC. difficilein the time-kill assay. The postantibiotic effect of CB-183,315 at 8× the MIC was 0.9 h. At 80× the MIC the postantibiotic effect was more than 6 h. In the hamster model of CDAD, CB-183,315 and vancomycin both demonstrated potent efficacy in resolving initial disease onset, even at very low doses. After the conclusion of dosing, CB-183,315 and vancomycin showed a similar dose- and time-dependent pattern with respect to rates of CDAD recurrence.

scholarly journals Pharmacodynamics of Daptomycin against Enterococcus faecium and Enterococcus faecalis in the Murine Thigh Infection Model

2018 ◽  
Vol 62 (10) ◽  
Author(s):  
James M. Kidd ◽  
Kamilia Abdelraouf ◽  
Tomefa E. Asempa ◽  
Romney M. Humphries ◽  
David P. Nicolau
Keyword(s):  
Enterococcus Faecalis ◽  
Enterococcus Faecium ◽  
Hill Equation ◽  
Infection Model ◽  
Free Drug Concentration ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time ◽  
The Hill ◽  
Susceptibility Breakpoint

ABSTRACT The Clinical and Laboratory Standards Institute (CLSI) daptomycin MIC susceptibility breakpoint for the treatment of enterococcal infections is ≤4 μg/ml. However, patients receiving daptomycin for the treatment of infections caused by enterococci with MICs of ≤4 μg/ml may experience treatment failures. We assessed the pharmacodynamics of daptomycin against enterococci in a neutropenic murine thigh infection model and determined the exposures necessary for bacteriostasis and a 1-log10-CFU reduction of Enterococcus faecalis and Enterococcus faecium. We further characterized daptomycin efficacy at clinically achievable exposures. Six E. faecium and 6 E. faecalis isolates (daptomycin MICs, 0.5 to 32 μg/ml) were studied. Daptomycin was administered at various doses over 24 h to achieve area under the free drug concentration-time curve-to-MIC ratios (fAUC0–24/MIC) ranging from 1 to 148. Daptomycin regimens that simulate mean human exposures following doses of 6, 8, and 10 mg/kg of body weight/day were also studied. Efficacy was assessed by the differences in the number of log10 CFU per thigh at 24 h. The Hill equation was used to estimate the fAUC0–24/MIC required to achieve bacteriostasis and a 1-log10-CFU reduction. For E. faecium, a 1-log10-CFU reduction required an fAUC0–24/MIC of 12.9 (R2 = 0.71). For E. faecalis, a 1-log10-CFU reduction was not achieved, while the fAUC0–24/MIC required for stasis was 7.2 (R2 = 0.8). With a human-simulated regimen of 6 mg/kg/day, a 1-log10-CFU reduction was observed in 3/3 E. faecium isolates with MICs of <4 μg/ml and 0/3 E. faecium isolates with MICs of ≥4 μg/ml; however, a 1-log10-CFU reduction was not achieved for any of the 6 E. faecalis isolates. These results, alongside clinical data, prompt a reevaluation of the current breakpoint.

scholarly journals Genotypic Analysis of Genes Associated with Independent Resistance and Cross-Resistance to Isoniazid and Ethionamide in Mycobacterium tuberculosis Clinical Isolates

2015 ◽  
Vol 59 (12) ◽  
pp. 7805-7810 ◽  
Author(s):  
Johana Rueda ◽  
Teresa Realpe ◽  
Gloria Isabel Mejia ◽  
Elsa Zapata ◽  
Juan Carlos Rozo ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Multidrug Resistant ◽  
Cross Resistance ◽  
Resistance Mutations ◽  
Content Type ◽  
Genotypic Analysis ◽  
Mdr Tb ◽  
Proportion Method ◽  
Emergence Of Resistance ◽  
Phenotypic Susceptibility

ABSTRACTEthionamide (ETH) is an antibiotic used for the treatment of multidrug-resistant (MDR) tuberculosis (TB) (MDR-TB), and its use may be limited with the emergence of resistance in theMycobacterium tuberculosispopulation. ETH resistance inM. tuberculosisis phenomenon independent or cross related when accompanied with isoniazid (INH) resistance. In most cases, resistance to INH and ETH is explained by mutations in theinhApromoter and in the following genes:katG,ethA,ethR,mshA,ndh, andinhA. We sequenced the above genes in 64M. tuberculosisisolates (n= 57 ETH-resistant MDR-TB isolates;n= 3 ETH-susceptible MDR-TB isolates; andn= 4 fully susceptible isolates). Each isolate was tested for susceptibility to first- and second-line drugs using the agar proportion method. Mutations were observed in ETH-resistant MDR-TB isolates at the following rates: 100% inkatG, 72% inethA, 45.6% inmshA, 8.7% inndh, and 33.3% ininhAor its promoter. Of the three ETH-susceptible MDR-TB isolates, all showed mutations inkatG; one had a mutation inethA, and another, inmshAandinhA. Finally, of the four fully susceptible isolates, two showed no detectable mutation in the studied genes, and two had mutations inmshAgene unrelated to the resistance. Mutations not previously reported were found in theethA,mshA,katG, andndhgenes. The concordance between the phenotypic susceptibility testing to INH and ETH and the sequencing was 1 and 0.45, respectively. Among isolates exhibiting INH resistance, the high frequency of independent resistance and cross-resistance with ETH in theM. tuberculosisisolates suggests the need to confirm the susceptibility to ETH before considering it in the treatment of patients with MDR-TB.

scholarly journals Mutations Associated with Reduced Surotomycin Susceptibility in Clostridium difficile and Enterococcus Species

2015 ◽  
Vol 59 (7) ◽  
pp. 4139-4147 ◽  
Author(s):  
Hannah M. Adams ◽  
Xiang Li ◽  
Carmela Mascio ◽  
Laurent Chesnel ◽  
Kelli L. Palmer
Keyword(s):  
Clostridium Difficile ◽  
Sequence Data ◽  
Acyl Carrier Protein ◽  
Serial Passage ◽  
Restriction Endonuclease Analysis ◽  
Health Concern ◽  
Content Type ◽  
Cyclic Lipopeptide ◽  
Illumina Sequence

ABSTRACTClostridium difficileinfection (CDI) is an urgent public health concern causing considerable clinical and economic burdens. CDI can be treated with antibiotics, but recurrence of the disease following successful treatment of the initial episode often occurs. Surotomycin is a rapidly bactericidal cyclic lipopeptide antibiotic that is in clinical trials for CDI treatment and that has demonstrated superiority over vancomycin in preventing CDI relapse. Surotomycin is a structural analogue of the membrane-active antibiotic daptomycin. Previously, we utilizedin vitroserial passage experiments to deriveC. difficilestrains with reduced surotomycin susceptibilities. The parent strains used included ATCC 700057 and clinical isolates from the restriction endonuclease analysis (REA) groups BI and K. Serial passage experiments were also performed with vancomycin-resistant and vancomycin-susceptibleEnterococcus faeciumandEnterococcus faecalis. The goal of this study is to identify mutations associated with reduced surotomycin susceptibility inC. difficileand enterococci. Illumina sequence data generated for the parent strains and serial passage isolates were compared. We identified nonsynonymous mutations in genes coding for cardiolipin synthase inC. difficileATCC 700057, enoyl-(acyl carrier protein) reductase II (FabK) and cell division protein FtsH2 inC. difficileREA type BI, and a PadR family transcriptional regulator inC. difficileREA type K. Among the 4 enterococcal strain pairs, 20 mutations were identified, and those mutations overlap those associated with daptomycin resistance. These data give insight into the mechanism of action of surotomycin againstC. difficile, possible mechanisms for resistance emergence during clinical use, and the potential impacts of surotomycin therapy on intestinal enterococci.

scholarly journals Investigations of the Mode of Action and Resistance Development of Cadazolid, a New Antibiotic for Treatment of Clostridium difficile Infections

2013 ◽  
Vol 58 (2) ◽  
pp. 901-908 ◽  
Author(s):  
Hans H. Locher ◽  
Patrick Caspers ◽  
Thierry Bruyère ◽  
Susanne Schroeder ◽  
Philippe Pfaff ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Clostridium Difficile ◽  
Dna Synthesis ◽  
Mode Of Action ◽  
Cross Resistance ◽  
Resistance Development ◽  
Content Type ◽  
Inhibition Of Protein Synthesis ◽  
Inhibitor Of Protein Synthesis ◽  
Inhibition Of Dna Synthesis

ABSTRACTCadazolid is a new oxazolidinone-type antibiotic currently in clinical development for the treatment ofClostridium difficile-associated diarrhea. Here, we report investigations on the mode of action and the propensity for spontaneous resistance development inC. difficilestrains. Macromolecular labeling experiments indicated that cadazolid acts as a potent inhibitor of protein synthesis, while inhibition of DNA synthesis was also observed, albeit only at substantially higher concentrations of the drug. Strong inhibition of protein synthesis was also obtained in strains resistant to linezolid, in agreement with low MICs against such strains. Inhibition of protein synthesis was confirmed in coupled transcription/translation assays using extracts from differentC. difficilestrains, including strains resistant to linezolid, while inhibitory effects in DNA topoisomerase assays were weak or not detectable under the assay conditions. Spontaneous resistance frequencies of cadazolid were low in all strains tested (generally <10−10at 2× to 4× the MIC), and in multiple-passage experiments (up to 13 passages) MICs did not significantly increase. Furthermore, no cross-resistance was observed, as cadazolid retained potent activity against strains resistant or nonsusceptible to linezolid, fluoroquinolones, and the new antibiotic fidaxomicin. In conclusion, the data presented here indicate that cadazolid acts primarily by inhibition of protein synthesis, with weak inhibition of DNA synthesis as a potential second mode of action, and suggest a low potential for spontaneous resistance development.

scholarly journals AsnB is responsible for peptidoglycan precursor amidation in Clostridium difficile in the presence of vancomycin

Microbiology ◽  
2020 ◽  
Vol 166 (6) ◽  
pp. 567-578 ◽  
Author(s):  
Fariza Ammam ◽  
Delphine Patin ◽  
Héloise Coullon ◽  
Didier Blanot ◽  
Thierry Lambert ◽  
...  
Keyword(s):  
Clostridium Difficile ◽  
Gene Cluster ◽  
Enterococcus Faecalis ◽  
Type Species ◽  
Asparagine Synthetase ◽  
Structure Modification ◽  
Content Type ◽  
E Coli ◽  
Link Type ◽  
Peptidoglycan Structure

Clostridium difficile 630 possesses a cryptic but functional gene cluster vanG Cd homologous to the vanG operon of Enterococcus faecalis . Expression of vanG Cd in the presence of subinhibitory concentrations of vancomycin is accompanied by peptidoglycan amidation on the meso-DAP residue. In this paper, we report the presence of two potential asparagine synthetase genes named asnB and asnB2 in the C. difficile genome whose products were potentially involved in this peptidoglycan structure modification. We found that asnB expression was only induced when C. difficile was grown in the presence of vancomycin, yet independently from the vanG Cd resistance and regulation operons. In addition, peptidoglycan precursors were not amidated when asnB was inactivated. No change in vancomycin MIC was observed in the asnB mutant strain. In contrast, overexpression of asnB resulted in the amidation of most of the C. difficile peptidoglycan precursors and in a weak increase of vancomycin susceptibility. AsnB activity was confirmed in E. coli . In contrast, the expression of the second asparagine synthetase, AsnB2, was not induced in the presence of vancomycin. In summary, our results demonstrate that AsnB is responsible for peptidoglycan amidation of C. difficile in the presence of vancomycin.

scholarly journals β-Lactams Enhance Daptomycin Activity against Vancomycin-Resistant Enterococcus faecalis and Enterococcus faecium inIn VitroPharmacokinetic/Pharmacodynamic Models

2015 ◽  
Vol 59 (5) ◽  
pp. 2842-2848 ◽  
Author(s):  
Jordan R. Smith ◽  
Katie E. Barber ◽  
Animesh Raut ◽  
Michael J. Rybak
Keyword(s):  
Body Weight ◽  
Combination Therapy ◽  
Enterococcus Faecalis ◽  
Enterococcus Faecium ◽  
Single Agent ◽  
Vancomycin Resistant Enterococcus ◽  
Content Type ◽  
Vancomycin Resistant ◽  
Combination Regimens

ABSTRACTEnterococcus faecalisandEnterococcus faeciumare frequently resistant to vancomycin and β-lactams. In enterococcal infections with reduced glycopeptide susceptibility, combination therapy is often administered. Our objective was to conduct pharmacokinetic/pharmacodynamic (PK/PD) models to evaluate β-lactam synergy with daptomycin (DAP) against resistant enterococci. OneE. faecalisstrain (R6981) and twoE. faeciumstrains (R6370 and 8019) were evaluated. DAP MICs were obtained. All strains were evaluated for response to LL37, an antimicrobial peptide, in the presence and absence of ceftaroline (CPT), ertapenem (ERT), and ampicillin (AMP). After 96 h,in vitromodels were run simulating 10 mg DAP/kg body weight/day, 600 mg CPT every 8 h (q8h), 2 g AMP q4h, and 1 g ERT q24h, both alone and in combination against all strains. DAP MICs were 2, 4, and 4 μg/ml for strains R6981, R6370, and 8019, respectively. PK/PD models demonstrated bactericidal activity with DAP-CPT, DAP-AMP, and DAP-ERT combinations against strain 8019 (P< 0.001 and log10CFU/ml reduction of >2 compared to any single agent). Against strains R6981 and R6370, the DAP-AMP combination demonstrated enhancement against R6370 but not R6981, while the combinations of DAP-CPT and DAP-ERT were bactericidal, demonstrated enhancement, and were statistically superior to all other regimens at 96 h (P< 0.001) against both strains. CPT, ERT, and AMP similarly augmented LL37 killing against strain 8019. In strains R6981 and R6370, CPT and ERT aided LL37 more than AMP (P< 0.001). Compared to DAP alone, combination regimens provide better killing and prevent resistance. Clinical research involving DAP combinations is warranted.

scholarly journals Impact of Daptomycin Dose Exposure Alone or in Combination with β-Lactams or Rifampin against Vancomycin-Resistant Enterococci in an In Vitro Biofilm Model

2020 ◽  
Vol 64 (5) ◽  
Author(s):  
Seyedehameneh Jahanbakhsh ◽  
Nivedita B. Singh ◽  
Juwon Yim ◽  
Razieh Kebriaei ◽  
Jordan R. Smith ◽  
...  
Keyword(s):  
Bactericidal Activity ◽  
Enterococcus Faecium ◽  
Biofilm Reactor ◽  
Content Type ◽  
Biofilm Model ◽  
Vancomycin Resistant Enterococci ◽  
Dosing Regimens ◽  
Vancomycin Resistant ◽  
Reactor Models

ABSTRACT Enterococcus faecium strains are commonly resistant to vancomycin and β-lactams. In addition, E. faecium often causes biofilm-associated infections and these infections are difficult to treat. In this context, we investigated the activity of dosing regimens using daptomycin (DAP) (8, 10, 12, and 14 mg/kg of body weight/day) alone and in combination with ceftaroline (CPT), ampicillin (AMP), ertapenem (ERT), and rifampin (RIF) against 2 clinical strains of biofilm-producing vancomycin-resistant Enterococcus faecium (VREfm), namely, strains S447 and HOU503, in an in vitro biofilm model. HOU503 harbors common LiaS and LiaR substitutions, whereas S447 lacks mutations associated with the LiaFSR pathway. MIC results demonstrated that both strains were susceptible to DAP and resistant to CPT, AMP, ERT, and RIF. The 168-h pharmacokinetic/pharmacodynamic (PK/PD) CDC biofilm reactor models (simulating human antibiotic exposures) were used with titanium and polyurethane coupons to evaluate the efficacy of antibiotic combinations. DAP 12 and 14 achieved bactericidal activity against S447 but lacked such effect against HOU503. Addition of ERT and RIF enhanced DAP activity, allowing DAP 8 and 10 plus ERT or RIF to produce bactericidal activity against both strains at 168 h. While DAP 8 and 10 plus CPT improved killing, they did not reach bactericidal reduction against S447. Combination of AMP, CPT, ERT, or RIF resulted in enhanced and bactericidal activity for DAP against HOU503 at 168 h. Our data provide further support for the use of combinations of DAP with AMP, ERT, CPT, and RIF in infections caused by biofilm producing VREfm. Further research involving DAP combinations against biofilm-producing enterococci is warranted.

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