30 results on '"Smith, Jordan R."'
Search Results
2. Impact of a pharmacist-driven care package on Staphylococcus aureus bacteremia management in a large community healthcare network: A propensity score-matched, quasi-experimental study
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Smith, Jordan R., Frens, Jeremy J., Snider, Cynthia B., and Claeys, Kimberly C.
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- 2018
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3. Time-kill determination of the bactericidal activity of telavancin and vancomycin against clinical methicillin-resistant Staphylococcus aureus isolates from cancer patients
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Rolston, Kenneth VI, Wang, Weiqun, Nesher, Lior, Smith, Jordan R., Rybak, Michael J., and Prince, Randall A.
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- 2017
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4. New Guidelines Endorse Old Recommendations for Invasive Enterococcal Infections
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Werth, Brian J., Smith, Jordan R., and Sakoulas, George
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- 2016
5. Real-World Experience with Oritavancin Therapy in Invasive Gram-Positive Infections
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Stewart, Cassie L., Turner, Michelle S., Frens, Jeremy J., Snider, Cynthia B., and Smith, Jordan R.
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- 2017
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6. Evaluation of Pharmacodynamic Interactions Between Telavancin and Aztreonam or Piperacillin/Tazobactam Against Pseudomonas aeruginosa, Escherichia coli and Methicillin-Resistant Staphylococcus aureus
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Yim, Juwon, Smith, Jordan R., Barber, Katie E., Hallesy, Jessica A., and Rybak, Michael J.
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- 2016
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7. Dalbavancin: A Novel Lipoglycopeptide Antibiotic with Extended Activity Against Gram-Positive Infections
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Smith, Jordan R., Roberts, Karrine D., and Rybak, Michael J.
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- 2015
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8. High-Dose Daptomycin Therapy for Staphylococcal Endocarditis and When to Apply It
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Smith, Jordan R., Claeys, Kimberly C., Barber, Katie E., and Rybak, Michael J.
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- 2014
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9. Evaluation of tedizolid against Staphylococcus aureus and enterococci with reduced susceptibility to vancomycin, daptomycin or linezolid
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Barber, Katie E., Smith, Jordan R., Raut, Animesh, and Rybak, Michael J.
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- 2016
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10. β-Lactam combinations with daptomycin provide synergy against vancomycin-resistant Enterococcus faecalis and Enterococcus faecium
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Smith, Jordan R., Barber, Katie E., Raut, Animesh, Aboutaleb, Mostafa, Sakoulas, George, and Rybak, Michael J.
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- 2015
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11. 442. Risk Score for Vancomycin-Associated Acute Kidney Injury in Hospitalized Patients with Acute Bacterial Skin and Skin Structure Infections
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Jorgensen, Sarah C J, Alosaimy, Sara, Lagnf, Abdalhamid M, Murray, Kyle P, Melvin, Sarah, Shamim, Muhammad-Daniayl, Brade, Karrine, Simon, Samuel, Nagel, Jerod, Smith, Jordan R, Williams, Karen, Huang, David B, Davis, Susan L, and Rybak, Michael J
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Abstracts ,Poster Abstracts - Abstract
Background Vancomycin (VAN) has been the standard empiric antibiotic for the treatment of hospitalized patients with acute bacterial skin and skin structure infections (ABSSSI) for decades but its use can be complicated by acute kidney injury (AKI). The substantial morbidity and mortality associated with AKI underscores the need to identify ABSSSI patients at increased risk for this complication. The objective of this study was to derive a clinical prediction model for VAN-associated AKI (VAN-AKI) in hospitalized patients with ABSSSI and at least one baseline traditional risk factor for AKI. Methods This was a multicenter, retrospective, case–control study between 2015 and 2018 conducted at seven academic medical centers in the USA. The population of interest was hospitalized adults with ABSSSI treated with VAN ≥72 h and initiated ≤24 h of admission. Cases consisted of patients who developed AKI according to the RIFLE criteria during VAN or ≤72 h of discontinuation. Patients who did not develop AKI served as controls. Independent predictors of VAN-AKI were identified through multivariable logistic regression. A risk score was derived using a weighted coefficient-based scoring system. Results A total of 284 patients (28 cases and 256 controls) were included. Independent predictors of VAN-AKI included in the score were: metastatic cancer, ICU admission at VAN initiation, alcohol abuse, ≥2 nephrotoxins, mental health disease, lower extremity ABSSSI and prior ABSSSI within 1 year. Patients with mental health disease had a variety of advanced chronic comorbidities and substance use. The median risk score in cases and controls was 9 (7, 11) and 4 (3.7) (P < 0.001), respectively. The risk score area under the receiver operator curve was 0.803 (95% CI 0.712, 0.894). The sensitivity, specificity, positive predictive value and negative predictive value of the risk score using a threshold of 5 points was 89.29% (95% CI 70.63%, 97.19%), 51.56% (42.27%, 57.81%), 16.78% (11.35%, 23.97%) and 97.78% (93.14%, 99.42%), respectively. Conclusion The risk score developed in this study provides a standardized, evidenced-based approach to identify hospitalized patients with ABSSSI at higher risk for VAN-AKI. External validation is required before widespread use. Disclosures All authors: No reported disclosures.
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- 2019
12. Imipenem‐Cilastatin‐Relebactam: A Novel β‐Lactam–β‐Lactamase Inhibitor Combination for the Treatment of Multidrug‐Resistant Gram‐Negative Infections.
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Smith, Jordan R., Rybak, Jeffrey M., and Claeys, Kimberly C.
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CEFTAZIDIME , *URINARY tract infections , *INTRA-abdominal infections , *PSEUDOMONAS aeruginosa , *BIOCHEMICAL mechanism of action - Abstract
Imipenem‐cilastatin‐relebactam (IMI‐REL) is a novel β‐lactam–β‐lactamase inhibitor combination recently approved for the treatment of complicated urinary tract infections (cUTIs) and complicated intraabdominal infections (cIAIs). Relebactam is a β‐lactamase inhibitor with the ability to inhibit a broad spectrum of β‐lactamases such as class A and class C β‐lactamases, including carbapenemases. The addition of relebactam to imipenem restores imipenem activity against several imipenem‐resistant bacteria, including Enterobacteriaceae and Pseudomonas aeruginosa. Clinical data demonstrate that IMI‐REL is well tolerated and effective in the treatment of cUTIs and cIAIs due to imipenem‐resistant bacteria. In a phase III trial comparing IMI‐REL with imipenem plus colistin, favorable clinical response was achieved in 71% and 70% of patients, respectively. Available clinical and pharmacokinetic data support the approved dosage of a 30‐minute infusion of imipenem 500 mg–cilastatin 500 mg–relebactam 250 mg every 6 hours, along with dosage adjustments based on renal function. In this review, we describe the chemistry, mechanism of action, spectrum of activity, pharmacokinetics and pharmacodynamics, and clinical efficacy, and safety and tolerability of this new agent. The approval of IMI‐REL represents another important step in the ongoing fight against multidrug‐resistant gram‐negative pathogens. [ABSTRACT FROM AUTHOR]
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- 2020
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13. Parenteral Fosfomycin for the Treatment of Multidrug Resistant Bacterial Infections: The Rise of the Epoxide.
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Trinh, Trang D., Smith, Jordan R., and Rybak, Michael J.
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FOSFOMYCIN , *BACTERIAL diseases , *LACTAMS , *GRAM-negative bacteria , *GRAM-positive bacteria , *BIOCHEMICAL mechanism of action , *MULTIDRUG-resistant tuberculosis - Abstract
Fosfomycin was initially discovered in 1969 but has recently gained renewed interest for the treatment of multidrug‐resistant (MDR) bacterial infections, particularly in the United States. Its unique mechanism of action, bactericidal activity, broad spectrum of activity, and relatively safe and tolerable adverse effect profile make it a great addition to the dwindling antibiotic armamentarium. Fosfomycin contains a three‐membered epoxide ring with a direct carbon to phosphorous bond that bypasses the intermediate oxygen bond commonly present in other organophosphorous compounds; this structure makes the agent unique from other antibiotics. Despite nearly 50 years of parenteral fosfomycin use in Europe, fosfomycin has retained stable activity against most pathogens. Furthermore, fosfomycin demonstrated in vitro synergy in combination with other cell wall–active antibiotics (e.g., β‐lactams, daptomycin). These combinations may offer respite for severe infections due to MDR gram‐positive and gram‐negative bacteria. The intravenous (IV) formulation is currently under review in the United States, and apropos, this review collates more contemporary evidence (i.e., studies published between 2000 and early 2019) in anticipation of this development. The approval of IV fosfomycin provides another option for consideration in the management of MDR infections. Its unique structure will give rise to a promising epoxide epoch in the battle against MDR bacteria. [ABSTRACT FROM AUTHOR]
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- 2019
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14. An Optimized De-Noising Scheme Based on the Null Hypothesis of Intrinsic Mode Functions.
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Smith, Jordan R., Al-Badrawi, Mahdi H., and Kirsch, Nicholas J.
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NULL hypothesis ,HILBERT-Huang transform ,NEWTON-Raphson method ,MODE shapes ,SIGNAL filtering ,PARAMETER estimation ,COMPUTATIONAL complexity - Abstract
Empirical mode decomposition (EMD) offers a data-driven approach for signal filtering. In this letter, a new de-noising scheme is proposed, which estimates a pertinent probability distribution parameter with the Newton-Raphson root-finding method. The parameter estimation reduces the computational cost of relevant mode selection by reducing the range of possible mode distribution shapes. Computational complexity is assessed, revealing significant reduction in the number of operations required in comparison to a previous de-noising scheme which utilized the same form of statistical filtering. Furthermore, simulation results of the proposed EMD filter show superior performance over other EMD de-noising techniques with real biomedical recordings corrupted by colored noise. [ABSTRACT FROM AUTHOR]
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- 2019
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15. Evaluation of dalbavancin alone and in combination with β-lactam antibiotics against resistant phenotypes of Staphylococcus aureus.
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Xhemali, Xhilda, Smith, Jordan R, Kebriaei, Razieh, Rice, Seth A, Stamper, Kyle C, Compton, Matthew, Singh, Nivedita B, Jahanbakhsh, Seyedehameneh, and Rybak, Michael J
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METHICILLIN-resistant staphylococcus aureus , *ANTIBACTERIAL agents , *GRAM-positive bacteria , *STAPHYLOCOCCUS aureus , *DRUG resistance in bacteria - Abstract
Background: Emergence of reduced susceptibility to vancomycin warrants the development of new antimicrobial agents for the treatment of MRSA. We evaluated the activity of dalbavancin, a novel lipoglycopeptide antibiotic, both alone and combined with β-lactams, in combination MIC testing and time-kill assays against resistant phenotypes of Staphylococcus aureus.Methods: S. aureus isolates included 50 organisms with varying susceptibility patterns. Dalbavancin was tested alone and in combination with five β-lactams: cefazolin, cefepime, ceftaroline, ertapenem and oxacillin. MIC values of the antibiotics were determined for all isolates. After initial MIC testing, dalbavancin MICs were determined in the presence of 0.5 × MIC of each β-lactam to determine the effect of each β-lactam on dalbavancin MIC. Time-kill assays were performed with dalbavancin and β-lactams tested at 0.5 × MIC for randomly selected organisms representing each MRSA phenotype. Time-kill curves were generated by plotting mean colony counts (log10 cfu/mL) versus time.Results: Dalbavancin MIC50 was 0.0313 mg/L and MIC90 was 0.0625 mg/L. Dalbavancin MICs decreased by zero to greater than five 2-fold dilutions in combination with each β-lactam. In time-kill assays, dalbavancin was synergistic with cefazolin, cefepime and ertapenem against all strains and the combination of dalbavancin and ceftaroline was synergistic against all but one. The combination of dalbavancin and oxacillin was synergistic against 5/8 strains.Conclusions: Dalbavancin was active against all MRSA strains tested, including heteroresistant vancomycin-intermediate S. aureus, vancomycin-intermediate S. aureus, daptomycin-non-susceptible and linezolid-resistant isolates. The synergy demonstrated against these organisms supports the use of dalbavancin in combination with β-lactams against resistant phenotypes of S. aureus. Further evaluation is warranted. [ABSTRACT FROM AUTHOR]- Published
- 2019
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16. Evaluation of daptomycin combinations with cephalosporins or gentamicin against Streptococcus mitis group strains in an in vitro model of simulated endocardial vegetations (SEVs).
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Juwon Yim, Smith, Jordan R., Singh, Nivedita B., Rice, Seth, Stamper, Kyle, Garcia de la Maria, Cristina, Bayer, Arnold S., Mishra, Nagendra N., Miró, José M., Tran, Truc T., Arias, Cesar A., Sullam, Paul, Rybak, Michael J., and Yim, Juwon
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VIRIDANS strepotococci , *ENDOCARDITIS , *DRUG allergy , *GENTAMICIN , *BETA lactam antibiotics , *ANTIBIOTICS , *BIOLOGICAL models , *CEPHALOSPORINS , *COMBINATION drug therapy , *PEPTIDE antibiotics , *RESEARCH funding , *STREPTOCOCCAL diseases , *STREPTOCOCCUS , *TREATMENT effectiveness - Abstract
Objectives: Among viridans group streptococcal infective endocarditis (IE), the Streptococcus mitis group is the most common aetiological organism. Treatment of IE caused by the S. mitis group is challenging due to the high frequency of β-lactam resistance, drug allergy and intolerability of mainstay antimicrobial agents such as vancomycin or gentamicin. Daptomycin has been suggested as an alternative therapeutic option in these scenarios based on its excellent susceptibility profile against S. mitis group strains . However, the propensity of many S. mitis group strains to rapidly evolve stable, high-level daptomycin resistance potentially limits this approach.Methods: We evaluated the activity of 6 mg/kg/day daptomycin alone or in combination with gentamicin, ceftriaxone or ceftaroline against two daptomycin-susceptible S. mitis group strains over 96 h in a pharmacokinetic/pharmacodynamic model of simulated endocardial vegetations.Results: Daptomycin alone was not bactericidal and high-level daptomycin resistance evolved at 96 h in both organisms. Combinations of daptomycin + ceftriaxone and daptomycin + ceftaroline demonstrated enhanced killing activity compared with each antibiotic alone and prevented emergence of daptomycin resistance at 96 h. Use of gentamicin as an adjunctive agent neither improved the efficacy of daptomycin nor prevented the development of daptomycin resistance.Conclusions: Addition of ceftriaxone or ceftaroline to daptomycin improves the bactericidal activity against S. mitis group strains and prevents daptomycin resistance emergence. Further investigation with combinations of daptomycin and β-lactams in a large number of strains is warranted to fully elucidate the clinical implications of such combinations for treatment of S. mitis group IE. [ABSTRACT FROM AUTHOR]- Published
- 2017
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17. Role of Combination Antimicrobial Therapy for Vancomycin-Resistant Enterococcus faecium Infections: Review of the Current Evidence.
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Yim, Juwon, Smith, Jordan R., and Rybak, Michael J.
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ANTI-infective agents , *ENTEROCOCCAL infections , *ENTEROCOCCUS , *VANCOMYCIN , *AMPICILLIN , *THERAPEUTICS - Abstract
Enterococcus species are the second most common cause of nosocomial infections in the United States and are particularly concerning in critically ill patients with preexisting comorbid conditions. Rising resistance to antimicrobials that were historically used as front-line agents for treatment of enterococcal infections, such as ampicillin, vancomycin, and aminoglycosides, further complicates the treatment of these infections. Of particular concern are Enterococcus faecium strains that are associated with the highest rate of vancomycin resistance. The introduction of antimicrobial agents with specific activity against vancomycin-resistant Enterococcus ( VRE) faecium including daptomycin, linezolid, quinupristin-dalfopristin, and tigecycline did not completely resolve this clinical dilemma. In this review, the mechanisms of action and resistance to currently available anti- VRE antimicrobial agents including newer agents such as oritavancin and dalbavancin will be presented. In addition, novel combination therapies including β-lactams and fosfomycin, and the promising results from in vitro , animal studies, and clinical experience in the treatment of VRE faecium will be discussed. [ABSTRACT FROM AUTHOR]
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- 2017
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18. Biofilm Time-Kill Curves to Assess the Bactericidal Activity of Daptomycin Combinations against Biofilm-Producing Vancomycin-Resistant Enterococcus faecium and faecalis.
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Barber, Katie E., Shammout, Zade, Smith, Jordan R., Kebriaei, Razieh, Morrisette, Taylor, and Rybak, Michael J.
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DAPTOMYCIN ,ENTEROCOCCUS faecium ,ENTEROCOCCUS faecalis ,MEDICAL equipment ,BIOFILMS - Abstract
Introduction: E. faecium and E. faecalis are responsible for 13.9% of hospital-acquired infections with frequent resistance to vancomycin (82.6% of E. faecium, 9.5% of E. faecalis). Medical device infections secondary to enterococci often require combination therapy due to impaired activity against biofilm embedded cells. In vitro data demonstrate synergistic activity of daptomycin combinations. Using a novel, biofilm time-kill approach, we evaluated whether daptomycin combinations maintained synergy against biofilm-producing E. faecium and E. faecalis. Methods: Broth microdilution (BMD) and biofilm MIC (bMIC) values for daptomycin, ampicillin, ceftriaxone, fosfomycin, and rifampin were determined against biofilm-producing E. faecium and E. faecalis. Daptomycin combination bMIC values were determined in the presence of biologic concentrations of other antimicrobials. Synergy was evaluated against two E. faecalis (R6981, R7808) and two E. faecium (5938 and 8019) using a previously described biofilm time-kill method. Synergy was defined as ≥2 log10 CFU/cm
2 reduction over the most active agent alone. Bactericidal activity was defined as ≥3 log10 CFU/cm2 reduction. Results: Daptomycin bMICs were 2–8-fold higher than BMD. In the presence of other antimicrobials, daptomycin bMICs were reduced ≥ two-fold in dilutions. Ceftriaxone and ampicillin demonstrated the most potent combinations with daptomycin, yielding synergy against three of four strains. Daptomycin plus rifampin was synergistic against E. faecium 5938 and E. faecalis 6981 and produced bactericidal kill. The combination of daptomycin plus fosfomycin displayed synergy solely against E. faecalis 6981. Conclusions: Daptomycin combinations with beta-lactams demonstrated promising synergistic activity against both E. faecium and E. faecalis. While daptomycin plus rifampin yielded bactericidal results, the effect was not seen across all organisms. These combinations warrant further evaluation to determine the optimal dose and response. [ABSTRACT FROM AUTHOR]- Published
- 2021
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19. House specials.
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Smith, Jordan R.
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CHICKEN as food - Abstract
Presents the recipe Chicken with Curried Lentils and Sweet Tomato-Fennel Confit.
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- 1995
20. A lipoglycopeptide antibiotic for Gram-positive biofilm-related infections.
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Blaskovich MAT, Hansford KA, Butler MS, Ramu S, Kavanagh AM, Jarrad AM, Prasetyoputri A, Pitt ME, Huang JX, Lindahl F, Ziora ZM, Bradford T, Muldoon C, Rajaratnam P, Pelingon R, Edwards DJ, Zhang B, Amado M, Elliott AG, Zuegg J, Coin L, Woischnig AK, Khanna N, Breidenstein E, Stincone A, Mason C, Khan N, Cho HK, Karau MJ, Greenwood-Quaintance KE, Patel R, Wootton M, James ML, Hutton ML, Lyras D, Ogunniyi AD, Mahdi LK, Trott DJ, Wu X, Niles S, Lewis K, Smith JR, Barber KE, Yim J, Rice SA, Rybak MJ, Ishmael CR, Hori KR, Bernthal NM, Francis KP, Roberts JA, Paterson DL, and Cooper MA
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- Animals, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, Biofilms, Glycopeptides pharmacology, Glycopeptides therapeutic use, Lipoglycopeptides therapeutic use, Mammals, Mice, Microbial Sensitivity Tests, Streptococcus pneumoniae, Vancomycin pharmacology, Vancomycin therapeutic use, Anti-Infective Agents pharmacology, Gram-Positive Bacterial Infections, Methicillin-Resistant Staphylococcus aureus
- Abstract
Drug-resistant Gram-positive bacterial infections are still a substantial burden on the public health system, with two bacteria ( Staphylococcus aureus and Streptococcus pneumoniae ) accounting for over 1.5 million drug-resistant infections in the United States alone in 2017. In 2019, 250,000 deaths were attributed to these pathogens globally. We have developed a preclinical glycopeptide antibiotic, MCC5145, that has excellent potency (MIC
90 ≤ 0.06 μg/ml) against hundreds of isolates of methicillin-resistant S. aureus (MRSA) and other Gram-positive bacteria, with a greater than 1000-fold margin over mammalian cell cytotoxicity values. The antibiotic has therapeutic in vivo efficacy when dosed subcutaneously in multiple murine models of established bacterial infections, including thigh infection with MRSA and blood septicemia with S. pneumoniae , as well as when dosed orally in an antibiotic-induced Clostridioides difficile infection model. MCC5145 exhibited reduced nephrotoxicity at microbiologically active doses in mice compared to vancomycin. MCC5145 also showed improved activity against biofilms compared to vancomycin, both in vitro and in vivo, and a low propensity to select for drug resistance. Characterization of drug action using a transposon library bioinformatic platform showed a mechanistic distinction from other glycopeptide antibiotics.- Published
- 2022
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21. Impact of Daptomycin Dose Exposure Alone or in Combination with β-Lactams or Rifampin against Vancomycin-Resistant Enterococci in an In Vitro Biofilm Model.
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Jahanbakhsh S, Singh NB, Yim J, Kebriaei R, Smith JR, Lev K, Tran TT, Rose WE, Arias CA, and Rybak MJ
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- Ampicillin pharmacology, Biofilms drug effects, Biofilms growth & development, Cephalosporins pharmacology, Drug Combinations, Ertapenem pharmacology, Humans, Microbial Sensitivity Tests, Ceftaroline, Anti-Bacterial Agents pharmacology, Daptomycin pharmacology, Enterococcus faecium drug effects, Rifampin pharmacology, Vancomycin-Resistant Enterococci drug effects, beta-Lactams pharmacology
- 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., (Copyright © 2020 American Society for Microbiology.)
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- 2020
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22. Combination of Tedizolid and Daptomycin against Methicillin-Resistant Staphylococcus aureus in an In Vitro Model of Simulated Endocardial Vegetations.
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Smith JR, Yim J, Rice S, Stamper K, Kebriaei R, and Rybak MJ
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- Drug Therapy, Combination, Anti-Bacterial Agents pharmacology, Daptomycin pharmacology, Endocarditis, Bacterial microbiology, Methicillin-Resistant Staphylococcus aureus drug effects, Oxazolidinones pharmacology, Tetrazoles pharmacology
- Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) is a major pathogen responsible for health care-associated infections, and treatment options are limited. Tedizolid (TZD) is a novel oxazolidinone antibiotic with activity against MRSA. Previously, daptomycin (DAP) has demonstrated synergy with other antibiotics against MRSA. We sought to determine the efficacy of the combination of TZD and DAP against MRSA in an in vitro model of simulated endocardial vegetations (SEVs). TZD simulations of 200 mg once daily and DAP simulations of 6 mg/kg of body weight and 10 mg/kg once daily were tested alone and in the combinations TZD plus DAP at 6 mg/kg or DAP at 10 mg/kg against two clinical strains of MRSA, 494 and 67. These regimens were tested in SEV models over 8 days to determine the antibacterial activity of the regimens and whether synergy or antagonism might be present between the agents. Against both strains 494 and 67 and at both DAP dose regimens, the combination of TZD and DAP was antagonistic at 192 h. In all cases, DAP alone was statistically superior to DAP plus TZD. When the combination was stopped after 96 h, transitioning to DAP at 6 mg/kg or DAP at 10 mg/kg alone resulted in better antibacterial activity than either of the TZD-plus-DAP combinations, further demonstrating antagonistic effects. Against MRSA, we demonstrated that TZD and DAP have antagonistic activity that hinders their overall antimicrobial efficacy. The exact nature of this antagonistic relationship is still undetermined, but its presence warrants further study of the potentially harmful grouping of the two antibiotics in clinical use., (Copyright © 2018 American Society for Microbiology.)
- Published
- 2018
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23. Evaluation of daptomycin combinations with cephalosporins or gentamicin against Streptococcus mitis group strains in an in vitro model of simulated endocardial vegetations (SEVs).
- Author
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Yim J, Smith JR, Singh NB, Rice S, Stamper K, Garcia de la Maria C, Bayer AS, Mishra NN, Miró JM, Tran TT, Arias CA, Sullam P, and Rybak MJ
- Subjects
- Drug Therapy, Combination, Endocarditis microbiology, Humans, Models, Biological, Streptococcal Infections microbiology, Treatment Outcome, Anti-Bacterial Agents administration & dosage, Cephalosporins administration & dosage, Daptomycin administration & dosage, Endocarditis drug therapy, Gentamicins administration & dosage, Streptococcal Infections drug therapy, Streptococcus mitis drug effects
- Abstract
Objectives: Among viridans group streptococcal infective endocarditis (IE), the Streptococcus mitis group is the most common aetiological organism. Treatment of IE caused by the S. mitis group is challenging due to the high frequency of β-lactam resistance, drug allergy and intolerability of mainstay antimicrobial agents such as vancomycin or gentamicin. Daptomycin has been suggested as an alternative therapeutic option in these scenarios based on its excellent susceptibility profile against S. mitis group strains . However, the propensity of many S. mitis group strains to rapidly evolve stable, high-level daptomycin resistance potentially limits this approach., Methods: We evaluated the activity of 6 mg/kg/day daptomycin alone or in combination with gentamicin, ceftriaxone or ceftaroline against two daptomycin-susceptible S. mitis group strains over 96 h in a pharmacokinetic/pharmacodynamic model of simulated endocardial vegetations., Results: Daptomycin alone was not bactericidal and high-level daptomycin resistance evolved at 96 h in both organisms. Combinations of daptomycin + ceftriaxone and daptomycin + ceftaroline demonstrated enhanced killing activity compared with each antibiotic alone and prevented emergence of daptomycin resistance at 96 h. Use of gentamicin as an adjunctive agent neither improved the efficacy of daptomycin nor prevented the development of daptomycin resistance., Conclusions: Addition of ceftriaxone or ceftaroline to daptomycin improves the bactericidal activity against S. mitis group strains and prevents daptomycin resistance emergence. Further investigation with combinations of daptomycin and β-lactams in a large number of strains is warranted to fully elucidate the clinical implications of such combinations for treatment of S. mitis group IE., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2017
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24. β-Lactamase Inhibitors Enhance the Synergy between β-Lactam Antibiotics and Daptomycin against Methicillin-Resistant Staphylococcus aureus.
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Henson KE, Yim J, Smith JR, Sakoulas G, and Rybak MJ
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- Ampicillin pharmacology, Microbial Sensitivity Tests, Penicillanic Acid analogs & derivatives, Penicillanic Acid pharmacology, Piperacillin pharmacology, Sulbactam pharmacology, Tazobactam, Anti-Bacterial Agents pharmacology, Daptomycin pharmacology, Methicillin-Resistant Staphylococcus aureus drug effects, beta-Lactamase Inhibitors pharmacology
- Abstract
The evidence for using combination therapy for the treatment of serious methicillin-resistant Staphylococcus aureus (MRSA) infections is growing. In this study, we investigated the synergistic effect of daptomycin (DAP) combined with piperacillin-tazobactam and ampicillin-sulbactam against MRSA in time-kill experiments. Six of eight strains demonstrated synergy between DAP and the β-lactam-β-lactamase inhibitor (BLI) combination. In 5/8 strains, the synergy occurred only in the presence of the BLI, highlighting a role for BLIs in peptide-β-lactam synergy., (Copyright © 2016 American Society for Microbiology.)
- Published
- 2016
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25. Daptomycin in Combination with Ceftolozane-Tazobactam or Cefazolin against Daptomycin-Susceptible and -Nonsusceptible Staphylococcus aureus in an In Vitro, Hollow-Fiber Model.
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Smith JR, Arya A, Yim J, Barber KE, Hallesy J, Singh NB, and Rybak MJ
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- Methicillin-Resistant Staphylococcus aureus drug effects, Microbial Sensitivity Tests, Penicillanic Acid pharmacology, Tazobactam, Anti-Bacterial Agents pharmacology, Cefazolin pharmacology, Cephalosporins pharmacology, Daptomycin pharmacology, Penicillanic Acid analogs & derivatives, Staphylococcus aureus drug effects
- Abstract
Ceftolozane-tazobactam (TOL-TAZ) is a novel cephalosporin/beta-lactamase inhibitor with activity against several Gram-negative pathogens. Daptomycin (DAP) has demonstrated synergistic activity with beta-lactams against methicillin-resistant Staphylococcus aureus (MRSA) isolates with reduced lipopeptide and glycopeptide susceptibilities. Our objective was to determine if DAP and TOL-TAZ possess synergy in hollow-fiber pharmacokinetic/pharmacodynamic (PK/PD) models. One isogenic pair of daptomycin-susceptible and daptomycin-nonsusceptible MRSA strains was evaluated. DAP, TOL-TAZ, and cefazolin (CFZ) MIC determinations were performed. DAP MIC determinations were also performed in the presence of subinhibitory concentrations of TOL-TAZ and CFZ. Ninety-six-hour in vitro models were run, simulating DAP at 10 mg/kg of body weight/day; TOL-TAZ at 1,500 mg every 8 h; TOL at 1,000 mg every 8 h; and DAP combined with TOL-TAZ (DAP+TOL-TAZ), DAP+TOL, DAP+TAZ, and DAP+CFZ at 2,000 mg every 8 h. DAP MICs were 0.5 and 4 μg/ml for strains R8845 and R8846, respectively. In the presence of CFZ, R8845 and R8846 DAP MICs were reduced 8-fold and 16-fold, respectively. TOL and TAZ had no effect on DAP MICs. PK/PD models demonstrated bactericidal activity with DAP+CFZ against both strains. The combination of DAP+TOL-TAZ was bactericidal against R8845 but was not bactericidal against daptomycin-nonsusceptible strain R8846. DAP+TOL and DAP+TAZ were not bactericidal. No other regimens were bactericidal. DAP+TOL-TAZ did not demonstrate synergistic activity against daptomycin-nonsusceptible S. aureus but prevented daptomycin-nonsusceptible MRSA emergence. Because DAP+TOL or TAZ alone did not prevent daptomycin-nonsusceptible MRSA emergence, the combination TOL-TAZ may be necessary for synergy with DAP. DAP+CFZ demonstrated enhancement against both strains. The combination of DAP+CFZ warrants further clinical study., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)
- Published
- 2016
- Full Text
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26. Oritavancin Combinations with β-Lactams against Multidrug-Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococci.
- Author
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Smith JR, Yim J, Raut A, and Rybak MJ
- Subjects
- Cefazolin pharmacology, Cephalosporins pharmacology, Daptomycin pharmacology, Drug Synergism, Ertapenem, Gram-Positive Bacterial Infections microbiology, Humans, Lipoglycopeptides, Methicillin-Resistant Staphylococcus aureus growth & development, Methicillin-Resistant Staphylococcus aureus isolation & purification, Microbial Sensitivity Tests, Nafcillin pharmacology, Staphylococcal Infections microbiology, Vancomycin pharmacology, Vancomycin-Resistant Enterococci growth & development, Vancomycin-Resistant Enterococci isolation & purification, Ceftaroline, Anti-Bacterial Agents pharmacology, Drug Resistance, Multiple, Bacterial drug effects, Glycopeptides pharmacology, Methicillin-Resistant Staphylococcus aureus drug effects, Vancomycin-Resistant Enterococci drug effects, beta-Lactams pharmacology
- Abstract
Oritavancin possesses activity against vancomycin-resistant enterococci (VRE) and methicillin-resistantStaphylococcus aureus(MRSA).In vitrodata suggest synergy between beta-lactams (BLs) and vancomycin or daptomycin, agents similar to oritavancin. We evaluated the activities of BLs combined with oritavancin against MRSA and VRE. Oritavancin MICs were determined for 30 strains, 5 each of MRSA, daptomycin-nonsusceptible (DNS) MRSA, vancomycin-intermediate MRSA (VISA), heteroresistant VISA (hVISA), vancomycin-resistantEnterococcus faecalis, and vancomycin-resistantEnterococcus faecium Oritavancin MICs were determined in the presence of subinhibitory concentrations of BLs. Oritavancin combined with ceftaroline, cefazolin, or nafcillin was evaluated for lethal synergy against MRSA, and oritavancin combined with ceftaroline, ampicillin, or ertapenem was evaluated for lethal synergy against VRE in 24-h time-kill assays. Oritavancin at 0.5× the MIC was combined with BLs at 0.5× the MIC or the biological free peak concentration, whichever one was lower. Synergy was defined as a ≥2-log10-CFU/ml difference between the killing achieved with the combination and that achieved with the most active single agent at 24 h. Oritavancin MICs were ≤0.125 μg/ml for all MRSA isolates except three VISA isolates with MICs of 0.25 μg/ml. Oritavancin MICs for VRE ranged from 0.03 to 0.125 μg/ml. Oritavancin in combination with ceftaroline was synergistic against all MRSA phenotypes and statistically superior to all other combinations against DNS MRSA, hVISA, and MRSA isolates (P< 0.02). Oritavancin in combination with cefazolin and oritavancin in combination with nafcillin were also synergistic against all MRSA strains. Synergy between oritavancin and all BLs was revealed against VRE strain 8019, while synergy between oritavancin and ampicillin or ertapenem but not ceftaroline was demonstrated against VRE strain R7164. The data support the potential use of oritavancin in combination with BLs, especially oritavancin in combination with ceftaroline, for the treatment of infections caused by MRSA. The data from the present study are not as strong for oritavancin in combination with BLs for VRE. Further study of both MRSA and VRE in more complex models is warranted., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)
- Published
- 2016
- Full Text
- View/download PDF
27. Telavancin demonstrates activity against methicillin-resistant Staphylococcus aureus isolates with reduced susceptibility to vancomycin, daptomycin, and linezolid in broth microdilution MIC and one-compartment pharmacokinetic/pharmacodynamic models.
- Author
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Smith JR, Barber KE, Hallesy J, Raut A, and Rybak MJ
- Subjects
- Microbial Sensitivity Tests, Staphylococcus aureus drug effects, Anti-Bacterial Agents pharmacology, Daptomycin pharmacology, Linezolid pharmacology, Methicillin-Resistant Staphylococcus aureus drug effects, Vancomycin pharmacology
- Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) isolates have arisen with reduced susceptibility to several anti-MRSA agents. Telavancin (TLV), a novel anti-MRSA agent, retains low MICs against these organisms. Our objective was to determine the MICs for TLV, daptomycin (DAP), vancomycin (VAN), and linezolid (LZD) against daptomycin-nonsusceptible (DNS) S. aureus, vancomycin-intermediate S. aureus (VISA), heteroresistant VISA (hVISA), and linezolid-resistant (LZD(r)) S. aureus. We also evaluated these agents against each phenotype in pharmacokinetic/pharmacodynamic (PK/PD) models. Seventy DNS, 100 VISA, 180 hVISA, and 25 LZD(r) MRSA isolates were randomly selected from our library and tested to determine their MICs against TLV, DAP, VAN, and LZD via broth microdilution and a Trek panel. Four isolates were randomly selected for 168-h in vitro models to evaluate treatment with TLV at 10 mg/kg of body weight/day, DAP at 10 mg/kg/day, VAN at 1 g every 12 h (q12h), and LZD at 600 mg q12h. The MIC50/90 for TLV, DAP, VAN, and LZD against 70 DNS S. aureus isolates were 0.06/0.125 μg/ml, 2/4 μg/ml, 1/2 μg/ml, and 2/2 μg/ml, respectively. Against 100 VISA isolates, the MIC50/90 were 0.06/0.125 μg/ml, 1/1 μg/ml, 4/8 μg/ml, and 1/2 μg/ml, respectively. Against 170 hVISA isolates, the MIC50/90 were 0.06/0.125 μg/ml, 0.5/1 μg/ml, 1/2 μg/ml, and 1/2 μg/ml, respectively. Against 25 LZD(r) isolates, the MIC50/90 were 0.03/0.06 μg/ml, 1/1 μg/ml, 2/2 μg/ml, and 8/8 μg/ml, respectively. The TLV MIC was >0.125 μg/ml for 10/365 (2.7%) isolates. In PK/PD models, TLV was universally bactericidal at 168 h and statistically superior to all antibiotics against DNS S. aureus strain R2334. These data further establish the potency of TLV against resistant MRSA. The model data demonstrate in vitro bactericidal activity of TLV against hVISA, VISA, DNS S. aureus, and LZD(r) S. aureus strains. Further clinical research is warranted., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
- Published
- 2015
- Full Text
- View/download PDF
28. Evaluation of Ceftaroline Alone and in Combination against Biofilm-Producing Methicillin-Resistant Staphylococcus aureus with Reduced Susceptibility to Daptomycin and Vancomycin in an In Vitro Pharmacokinetic/Pharmacodynamic Model.
- Author
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Barber KE, Smith JR, Ireland CE, Boles BR, Rose WE, and Rybak MJ
- Subjects
- Anti-Bacterial Agents pharmacokinetics, Cephalosporins pharmacokinetics, Daptomycin pharmacokinetics, Drug Therapy, Combination methods, Half-Life, Microbial Sensitivity Tests methods, Rifampin pharmacokinetics, Rifampin pharmacology, Vancomycin pharmacokinetics, Ceftaroline, Anti-Bacterial Agents pharmacology, Biofilms drug effects, Cephalosporins pharmacology, Daptomycin pharmacology, Methicillin pharmacology, Methicillin-Resistant Staphylococcus aureus drug effects, Vancomycin pharmacology
- Abstract
Annually, medical device infections are associated with >250,000 catheter-associated bloodstream infections (CLABSI), with up to 25% mortality. Staphylococcus aureus, a primary pathogen in these infections, is capable of biofilm production, allowing organism persistence in harsh environments, offering antimicrobial protection. With increases in S. aureus isolates with reduced susceptibility to current agents, ceftaroline (CPT) offers a therapeutic alternative. Therefore, we evaluated whether CPT would have a role against biofilm-producing methicillin-resistant S. aureus (MRSA), including those with decreased susceptibilities to alternative agents. In this study, we investigated CPT activity alone or combined with daptomycin (DAP) or rifampin (RIF) against 3 clinical biofilm-producing MRSA strains in an in vitro biofilm pharmacokinetic/pharmacodynamic (PK/PD) model. Simulated antimicrobial regimens were as follows: 600 mg of CPT every 8 h (q8h) (free maximum concentration of drug [fCmax], 17.04 mg/liter; elimination half-life [t1/2], 2.66 h), 12 mg/kg of body weight/day of DAP (fCmax, 14.7 mg/liter; t1/2, 8 h), and 450 mg of RIF q12h (fCmax, 3.5 mg/liter; t1/2, 3.4 h), CPT plus DAP, and CPT plus RIF. Samples were obtained and plated to determine colony counts. Differences in log10 CFU/cm(2) were evaluated by analysis of variance with Tukey's post hoc test. The strains were CPT and vancomycin susceptible and DAP nonsusceptible (DNS). CPT displayed activity throughout the experiment. DAP demonstrated initial activity with regrowth at 24 h in all strains. RIF was comparable to the drug-free control, and little benefit was observed when combined with CPT. CPT plus DAP displayed potent activity, with an average log10 CFU/cm(2) reduction of 3.33 ± 1.01 from baseline. CPT demonstrated activity against biofilm-producing DNS MRSA. CPT plus DAP displayed therapeutic enhancement over monotherapy, providing a potential option for difficult-to-treat medical device infections., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
- Published
- 2015
- Full Text
- View/download PDF
29. β-Lactams enhance daptomycin activity against vancomycin-resistant Enterococcus faecalis and Enterococcus faecium in in vitro pharmacokinetic/pharmacodynamic models.
- Author
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Smith JR, Barber KE, Raut A, and Rybak MJ
- Subjects
- Ampicillin pharmacology, Anti-Bacterial Agents pharmacology, Cephalosporins pharmacology, Ertapenem, Microbial Sensitivity Tests, Vancomycin-Resistant Enterococci drug effects, Ceftaroline, Daptomycin pharmacology, Enterococcus faecalis drug effects, Enterococcus faecium drug effects, Vancomycin pharmacology, beta-Lactams pharmacology
- Abstract
Enterococcus faecalis and Enterococcus faecium are 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. One E. faecalis strain (R6981) and two E. faecium strains (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 vitro models 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 log10 CFU/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., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
- Published
- 2015
- Full Text
- View/download PDF
30. Impact of the combination of daptomycin and trimethoprim-sulfamethoxazole on clinical outcomes in methicillin-resistant Staphylococcus aureus infections.
- Author
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Claeys KC, Smith JR, Casapao AM, Mynatt RP, Avery L, Shroff A, Yamamura D, Davis SL, and Rybak MJ
- Subjects
- Anti-Bacterial Agents adverse effects, Daptomycin adverse effects, Drug Synergism, Drug Therapy, Combination, Female, Humans, Male, Microbial Sensitivity Tests, Middle Aged, Retrospective Studies, Treatment Outcome, Trimethoprim, Sulfamethoxazole Drug Combination adverse effects, Anti-Bacterial Agents therapeutic use, Daptomycin therapeutic use, Methicillin-Resistant Staphylococcus aureus drug effects, Staphylococcal Infections drug therapy, Trimethoprim, Sulfamethoxazole Drug Combination therapeutic use
- Abstract
Complicated Staphylococcus aureus infections, including bacteremia, are often associated with treatment failures, prolonged hospital stays, and the emergence of resistance to primary and even secondary therapies. Daptomycin is commonly used as salvage therapy after vancomycin failure for the treatment of methicillin-resistant S. aureus (MRSA) infections. Unfortunately, the emergence of daptomycin resistance, especially in deep-seated infections, has been reported, prompting the need for alternative or combination therapy. Numerous antibiotic combinations with daptomycin have been investigated clinically and in vitro. Of interest, the combination of daptomycin and trimethoprim-sulfamethoxazole (TMP-SMX) has proved to be rapidly bactericidal in vitro to strains that are both susceptible and nonsusceptible to daptomycin. However, to date, there is limited clinical evidence supporting the use of this combination. This was a multicenter, retrospective case series of patients treated with the combination of daptomycin and TMP-SMX for at least 72 h. The objective of this study was to describe the safety and effectiveness of this regimen in clinical practice. The most commonly stated reason that TMP-SMX was added to daptomycin was persistent bacteremia and/or progressive signs and symptoms of infection. After the initiation of combination therapy, the median time to clearance of bacteremia was 2.5 days. Microbiological eradication was demonstrated in 24 out of 28 patients, and in vitro synergy was demonstrated in 17 of the 17 recovered isolates. Further research with this combination is necessary to describe the optimal role and its impact on patient outcomes., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
- Published
- 2015
- Full Text
- View/download PDF
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