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Karas JA, Carter GP, Howden BP, Turner AM, Paulin OKA, Swarbrick JD, Baker MA, Li J, Velkov T. Structure–Activity Relationships of Daptomycin Lipopeptides. J Med Chem 2020; 63:13266-13290. [DOI: 10.1021/acs.jmedchem.0c00780] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- John A. Karas
- Department of Pharmacology & Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC 3010, Australia
| | - Glen P. Carter
- Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia
| | - Benjamin P. Howden
- Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia
| | - Adrianna M. Turner
- Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia
| | - Olivia K. A. Paulin
- Department of Pharmacology & Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC 3010, Australia
| | - James D. Swarbrick
- Department of Pharmacology & Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC 3010, Australia
| | - Mark. A. Baker
- Priority Research Centre in Reproductive Science, School of Environmental and Life Sciences, University of Newcastle, Callaghan, NSW 2308, Australia
| | - Jian Li
- Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia
| | - Tony Velkov
- Department of Pharmacology & Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC 3010, Australia
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Ambrose PG. Antibacterial drug development program successes and failures: a pharmacometric explanation. Curr Opin Pharmacol 2017; 36:1-7. [PMID: 28688237 DOI: 10.1016/j.coph.2017.06.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Accepted: 06/17/2017] [Indexed: 10/19/2022]
Abstract
My thesis is a simple one. We have not been doing a good enough job selecting dose regimens for serious infections during the drug development process. If we are to do a better job in the future, we need to revisit some uncomfortable places. That is, some notable program failures. To be clear, we are not revisiting program failures to make anyone uncomfortable or cast aspersions - but rather so that we sow the seeds for a better future. To that end, we will examine program failures and successes through a pharmacometric lens. Through this powerful lens, we will come to understand that many of our failures were not only predictable, but perhaps expected and entirely avoidable. The goal of this communication is to set forth the type of thinking and data that is necessary for rational dose selection.
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Mayers DL, Sobel JD, Ouellette M, Kaye KS, Marchaim D. Antibiotic Resistance of Non-pneumococcal Streptococci and Its Clinical Impact. ANTIMICROBIAL DRUG RESISTANCE 2017. [PMCID: PMC7123568 DOI: 10.1007/978-3-319-47266-9_2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The taxonomy of streptococci has undergone major changes during the last two decades. The present classification is based on both phenotypic and genotypic data. Phylogenetic classification of streptococci is based on 16S rRNA sequences [1], and it forms the backbone of the overall classification system of streptococci. Phenotypic properties are also important, especially for clinical microbiologists. The type of hemolysis on blood agar, reaction with Lancefield grouping antisera, resistance to optochin, and bile solubility remain important for grouping of clinical Streptococcus isolates and therefore treatment options [2]. In the following chapter, two phenotypic classification groups, viridans group streptococci (VGS) and beta-hemolytic streptococci, will be discussed.
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Affiliation(s)
| | - Jack D. Sobel
- Wayne State University School of Medicine, Detroit Medical Center, Detroit, Michigan USA
| | - Marc Ouellette
- Canada Research Chair in Antimicrobial Resistance, Centre de recherche en Infectiologie, University of Laval, Quebec City, Canada
| | - Keith S. Kaye
- Division of Infectious Diseases, University of Michigan Medical School, Ann Arbor, Michigan USA
| | - Dror Marchaim
- Infection Control and Prevention Unit of Infectious Diseases, Assaf Harofeh Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel
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Kelesidis T. Origin of de novo daptomycin non susceptible enterococci. World J Clin Infect Dis 2015; 5:30-36. [DOI: 10.5495/wjcid.v5.i2.30] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Revised: 04/01/2015] [Accepted: 04/20/2015] [Indexed: 02/06/2023] Open
Abstract
The emergence of daptomycin non-susceptible enterococci (DNSE) poses both treatment and infection control challenges. Clinicians should be vigilant that DNSE may be isolated from patients with or without (de novo DNSE) prior use of daptomycin. Recent epidemiological data suggest the presence of a community reservoir for DNSE which may be associated with environmental, foodborne and agricultural exposures. The mechanisms of nonsusceptibility to daptomycin have not been well characterized and may not parallel those for Staphylococcus aureus. The identification of daptomycin resistance genes in anaerobes, in farm animals and in an ecosystem that has been isolated for million years, suggest that the environmental reservoir for de novo DNSE may be larger than previously thought. Herein, the limited available scientific evidence regarding the possible origin of de novo DNSE is discussed. The current existing evidence is not sufficient to draw firm conclusions on the origin of DNSE. Further studies to determine the mechanisms of de novo daptomycin nonsusceptibility among enterococci are needed.
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In vitro activity of daptomycin in combination with β-lactams, gentamicin, rifampin, and tigecycline against daptomycin-nonsusceptible enterococci. Antimicrob Agents Chemother 2015; 59:4279-88. [PMID: 25963982 DOI: 10.1128/aac.05077-14] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2015] [Accepted: 05/02/2015] [Indexed: 12/15/2022] Open
Abstract
Enterococci that are nonsusceptible (NS; MIC > 4 μg/ml) to daptomycin are an emerging clinical concern. The synergistic combination of daptomycin plus beta-lactams has been shown to be effective against vancomycin-resistant Enterococcus (VRE) species in vitro. This study systematically evaluated by in vitro time-kill studies the effect of daptomycin in combination with ampicillin, cefazolin, ceftriaxone, ceftaroline, ertapenem, gentamicin, tigecycline, and rifampin, for a collection of 9 daptomycin-NS enterococci that exhibited a broad range of MICs and different resistance-conferring mutations. We found that ampicillin plus daptomycin yielded the most consistent synergy but did so only for isolates with mutations to the liaFSR system. Daptomycin binding was found to be enhanced by ampicillin in a representative isolate with such mutations but not for an isolate with mutation to the yycFGHIJ system. In contrast, ampicillin enhanced the killing of the LL-37 human antimicrobial peptide against daptomycin-NS E. faecium with either the liaFSR or yycFGHIJ mutation. Antagonism was noted only for rifampin and tigecycline and only for 2 or 3 isolates. These data add support to the growing body of evidence indicating that therapy combining daptomycin and ampicillin may be helpful in eradicating refractory VRE infections.
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Principi N, Caironi M, Venturini F, Pani L, Esposito S. Daptomycin in paediatrics: current knowledge and the need for future research. J Antimicrob Chemother 2014; 70:643-8. [PMID: 25406298 DOI: 10.1093/jac/dku453] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
To overcome the problems stemming from antimicrobial resistance, there have been several attempts to develop new antimicrobials in recent years. Of the highly potent drugs targeting resistant Gram-positive bacteria, daptomycin has a number of attractive characteristics that suggest its possible use in the treatment of serious infections due to these organisms. Although several pharmacokinetic and clinical studies in adults have provided data to determine how this drug should be prescribed to obtain the maximal clinical efficacy without significant risks of severe adverse events, we have not yet solved all of the problems related to the use of this antibiotic in paediatric patients. In this paper, the resolved and lingering problems of daptomycin treatment in newborns and children are reviewed and discussed. Studies have indicated that daptomycin is a promising therapeutic option for the treatment of paediatric diseases caused by MDR Gram-positive bacilli. However, before daptomycin can be licensed for use in newborns and children, further studies are needed to establish the appropriate dosages for paediatric patients of different ages. The data collected in adults can only be transferred to children older than 12 years, and the information available is not sufficient to determine the dosage that will assure the highest antimicrobial efficacy with only marginal risks of adverse events in younger patients. Thus, studies in neonates and younger infants are urgently needed to permit the use of daptomycin in the first months of life, a period in which infections due to MDR Gram-positive pathogens are increasing.
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Affiliation(s)
- Nicola Principi
- Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Michela Caironi
- Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Francesca Venturini
- Pharmacy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Luca Pani
- Agenzia Italiana del Farmaco, Rome, Italy
| | - Susanna Esposito
- Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
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Hall Snyder A, Werth BJ, Barber KE, Sakoulas G, Rybak MJ. Evaluation of the novel combination of daptomycin plus ceftriaxone against vancomycin-resistant enterococci in an in vitro pharmacokinetic/pharmacodynamic simulated endocardial vegetation model. J Antimicrob Chemother 2014; 69:2148-54. [PMID: 24777900 DOI: 10.1093/jac/dku113] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
OBJECTIVES Daptomycin has demonstrated synergy with β-lactams against Enterococcus faecium and this combination has been used successfully to treat infections refractory to daptomycin. We investigated daptomycin alone and combined with ceftriaxone against vancomycin-resistant enterococci (VRE) in an in vitro pharmacokinetic/pharmacodynamic simulated endocardial vegetation (SEV) model. METHODS Daptomycin (6 and 12 mg/kg/day) with and without 2 g of ceftriaxone every 24 h were evaluated against two clinical E. faecium strains (8019 and 5938) and one Enterococcus faecalis (6981) in a 96 h in vitro pharmacokinetic/pharmacodynamic SEV model. FITC-labelled poly-l-lysine was used to assess β-lactam-induced changes in cell surface charge. RESULTS For 8019 and 6981, daptomycin 6 mg/kg with ceftriaxone and daptomycin 12 mg/kg alone and in combination with ceftriaxone displayed significantly more activity than daptomycin 6 mg/kg alone from 48 to 96 h (P ≤ 0.005). The addition of ceftriaxone significantly enhanced activity of daptomycin 6 mg/kg against both strains at 96 h (8019, reductions -0.55 versus 3.64 log10 cfu/g; 6981, reductions 1.11 versus 5.67 log10 cfu/g; P < 0.001) and improved daptomycin 12 mg/kg against 8019 at 96 h. Daptomycin 12 mg/kg plus ceftriaxone displayed no appreciable activity against 5938 (daptomycin MIC 32 mg/L). Daptomycin non-susceptibility developed in 8019 and 6981 versus daptomycin 6 mg/kg by 96 h. Ampicillin or ceftriaxone exposure reduced daptomycin surface charge in 8019, resulting in significantly increased FITC-poly-l-lysine binding. CONCLUSIONS The combination of daptomycin and ceftriaxone may be promising for eradicating high-inoculum, deep-seated enterococcal infections. Further research is warranted to examine the enhancement of daptomycin and innate immunity killing of VRE by ceftriaxone and other β-lactams.
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Affiliation(s)
- Ashley Hall Snyder
- Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, MI 48201, USA
| | - Brian J Werth
- Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, MI 48201, USA Department of Pharmacy, University of Washington, Seattle, WA 98195, USA
| | - Katie E Barber
- Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, MI 48201, USA
| | - George Sakoulas
- Department of Pediatrics, University of San Diego School of Medicine, San Diego, CA 92123, USA Infectious Diseases, Sharp Memorial Hospital, San Diego, CA 92123, USA
| | - Michael J Rybak
- Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, MI 48201, USA School of Medicine, Wayne State University, Detroit, MI 48201, USA
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Cilli F, Aydemir S, Tunger A. In VitroActivity of Daptomycin Alone and in Combination with Various Antimicrobials Against Gram-Positive Cocci. J Chemother 2013. [DOI: 10.1179/joc.2008.18.1.27] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
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Successful treatment of left sided native valve MRSA endocarditis in immunocompromised host treated with daptomycin and surgery: a case report. Indian J Thorac Cardiovasc Surg 2013. [DOI: 10.1007/s12055-013-0172-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
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Kelesidis T, Humphries R, Uslan DZ, Pegues DA. Daptomycin nonsusceptible enterococci: an emerging challenge for clinicians. Clin Infect Dis 2011; 52:228-34. [PMID: 21288849 PMCID: PMC8483151 DOI: 10.1093/cid/ciq113] [Citation(s) in RCA: 113] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2010] [Accepted: 11/02/2010] [Indexed: 12/17/2022] Open
Abstract
Daptomycin is the only antibiotic with in vitro bactericidal activity against vancomycin-resistant Enterococcus (VRE) that is approved by the Food and Drug Administration (FDA). Data on the potential emergence of daptomycin nonsusceptibility among enterococci remain limited. We systematically reviewed the published literature for reports of isolates of enterococci that were daptomycin nonsusceptible and assessed the clinical significance and outcome of therapy. Based on susceptibility breakpoints approved by the Clinical Laboratory Standards Institute (CLSI), daptomycin has in vitro activity against >90% of enterococcal isolates. Less than 2% of enterococcal isolates were daptomycin nonsusceptible, with minimum inhibitory concentrations (MICs) >4 μg/mL. The prevalence of nonsusceptibility of VRE isolates to daptomycin may be overestimated due to the spread of clonally related isolates in health care settings. Clinicians should be aware of the possibility of the emergence of daptomycin nonsusceptibility and should closely monitor daptomycin MICs of enterococci isolated during treatment.
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Affiliation(s)
- Theodoros Kelesidis
- Department of Medicine, Division of Infectious Diseases, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave., Los Angeles, CA 90095, USA.
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Batard E, Amirault E, Caroff N, Asseray N, Caillon J, Potel G. Relationship between autolysis and teicoplanin activity against Staphylococcus epidermidis. Int J Antimicrob Agents 2010; 36:574-5. [PMID: 20869851 DOI: 10.1016/j.ijantimicag.2010.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2010] [Accepted: 08/03/2010] [Indexed: 10/19/2022]
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Bouza E. New therapeutic choices for infections caused by methicillin-resistant Staphylococcus aureus. Clin Microbiol Infect 2010; 15 Suppl 7:44-52. [PMID: 19951334 DOI: 10.1111/j.1469-0691.2009.03091.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
In recent years, a marked increase in the incidence of infections caused by methicillin-resistant Staphylococcus aureus (MRSA) has occurred in many countries. This review addresses the effectiveness and limitations of drugs classically used for the treatment of MRSA, e.g. vancomycin, and also newer anti-MRSA antimicrobials, e.g. second-generation glycolipopeptides, tigecycline, and beta-lactams.
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Affiliation(s)
- E Bouza
- Servicio de Microbiología Clínica y E. Infecciosas, Hospital General Universitario Gregorio Marañón, Universidad Complutenste, Madrid, and Ciber de Enfermedades Respiratories (CIBERES), Spain.
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Duah M. Daptomycin for methicillin-resistant Staphylococcus epidermidis native-valve endocarditis: a case report. Ann Clin Microbiol Antimicrob 2010; 9:9. [PMID: 20167084 PMCID: PMC2836277 DOI: 10.1186/1476-0711-9-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2009] [Accepted: 02/18/2010] [Indexed: 11/10/2022] Open
Abstract
Coagulase-negative staphylococci (CoNS) have been increasing in importance as a cause of native valve endocarditis (NVE). Most cases of NVE caused by CoNS are attributable to Staphylococcus epidermidis. NVE caused by CoNS acquired in a nosocomial setting may differ from cases acquired in the community in several ways. It may be associated with hemodialysis, the presence of a long-term indwelling central catheter or pacemaker, or a recent invasive procedure; nosocomial cases may have a higher rate of methicillin resistance among CoNS isolates, and so be more likely to be treated with vancomycin. Unfortunately, NVE caused by methicillin-resistant CoNS has been associated with significantly higher rates of persistent bacteremia and in-hospital mortality than methicillin-susceptible isolates. The poor outcomes in these cases point to the need for alternative therapies with potent activity against methicillin-resistant CoNS. In our medical center, a 76-year-old man presented with native-valve endocarditis and positive blood cultures for methicillin-resistant Staphylococcus epidermidis (MRSE). During each of three 6-week courses of treatment with vancomycin, blood cultures were negative, but they once again became positive for MRSE when vancomycin was discontinued. The minimum inhibitory concentration of the MRSE isolates for vancomycin remained stable at 2 microg/mL. Eventually, treatment with daptomycin was initiated (500 mg [7 mg/kg]) 3 times/week for 6 weeks. Over the following year, no positive cultures for MRSE were detected.
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Goedecke VA, Clajus C, Burkhardt O, Martens-Lobenhoffer J, Bode-Böger SM, Kielstein JT, Hiss M. Pharmacokinetics and dialysate levels of daptomycin given intravenously in a peritoneal dialysis patient. ACTA ACUST UNITED AC 2009; 41:155-7. [DOI: 10.1080/00365540802613095] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Kanafani ZA, Federspiel JJ, Fowler VG. Infective endocarditis caused by daptomycin-resistant Enterococcus faecalis: A case report. ACTA ACUST UNITED AC 2009; 39:75-7. [PMID: 17366018 DOI: 10.1080/00365540600786465] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Daptomycin is a first-in-class antibiotic with efficacy against Gram-positive bacteria. We document the second report of daptomycin resistance in a clinical isolate of Enterococcus faecalis.
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Affiliation(s)
- Zeina A Kanafani
- Division of Infectious Diseases, Duke University Medical Center, Durham, NC 27710, USA
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Antibiotic Resistance of Non-Pneumococcal Streptococci and Its Clinical Impact. ANTIMICROBIAL DRUG RESISTANCE 2009. [PMCID: PMC7122742 DOI: 10.1007/978-1-60327-595-8_2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Viridans streptococci (VGS) form a phylogenetically heterogeneous group of species belonging to the genus Streptococcus (1). However, they have some common phenotypic properties. They are alfa- or non-haemolytic. They can be differentiated from S. pneumoniae by resistance to optochin and the lack of bile solubility (2). They can be differentiated from the Enterococcus species by their inability to grow in a medium containing 6.5% sodium chloride (2). Earlier, so-called nutritionally variant streptococci were included in the VGS but based on the molecular data they have now been removed to a new genus Abiotrophia (3) and are not included in the discussion below. VGS belong to the normal microbiota of the oral cavities and upper respiratory tracts of humans and animals. They can also be isolated from the female genital tract and all regions of the gastrointestinal tract (2, 3). Several species are included in VGS and are listed elsewhere (2, 3). Clinically the most important species belonging to the VGS are S. mitis, S. sanguis and S. oralis.
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Malli E, Spiliopoulou I, Kolonitsiou F, Klapsa D, Giannitsioti E, Pantelidi K, Pratti A, Panopoulou M, Grapsa S, Alepopoulou E, Neonakis I, Frantzidou F, Alexiou-Daniel S, Bakola D, Koutsia-Carouzou C, Malamou-Lada H, Zerva L, Vlahaki E, Kartali-Ktenidou S, Anastassiou ED, Petinaki E. In vitro activity of daptomycin against Gram-positive cocci: the first multicentre study in Greece. Int J Antimicrob Agents 2008; 32:525-8. [PMID: 18774268 DOI: 10.1016/j.ijantimicag.2008.05.020] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2008] [Revised: 05/28/2008] [Accepted: 05/29/2008] [Indexed: 11/26/2022]
Abstract
A total of 10420 Gram-positive cocci (including staphylococci, enterococci and various groups of streptococci) collected from clinically significant specimens in ten Greek hospitals during 2006--2007 were tested for their susceptibility to daptomycin. The minimum inhibitory concentration (MIC) was determined by the broth microdilution method. Daptomycin demonstrated very high activity against Enterococcus faecalis (MIC at which 50% of the isolates were inhibited (MIC50) = 1mg/L and MIC at which 90% of the isolates were inhibited (MIC90) = 1.36 mg/L), Enterococcus faecium (MIC50 = 1.36 mg/L and MIC90 = 1.90 mg/L), Streptococcus pyogenes (MIC50 = 0.12 mg/L and MIC90 = 0.50mg/L), Streptococcus agalactiae (MIC50 = 0.09 mg/L and MIC90 = 0.12 mg/L), Streptococcus pneumoniae (MIC50 = 0.24 mg/L and MIC90 = 0.5 mg/L) and viridans group streptococci (MIC50 = 0.50 mg/L and MIC90 = 0.89 mg/L). Resistance to linezolid and vancomycin for enterococci and to penicillin for streptococci appears to be independent of reduced susceptibility to daptomycin. On the other hand, daptomycin was also active against meticillin-resistant Staphylococcus aureus (MIC50 = 0.44 mg/L and MIC90 = 0.78 mg/L) and meticillin-resistant coagulase-negative staphylococci (MIC50 = 0.24 mg/L and MIC90 = 0.44 mg/L); however, 0.9% of the staphylococci tested had an MIC > 1mg/L, which is the Clinical and Laboratory Standards Institute breakpoint proposed for susceptibility. For all tested organism groups, resistance to daptomycin was not associated with glycopeptide resistance.
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Affiliation(s)
- E Malli
- Department of Microbiology, University Hospital of Larissa, Larissa, Greece
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Jørgen B, Merckoll P, Melby KK. Susceptibility to daptomycin, quinupristin-dalfopristin and linezolid and some other antibiotics in clinical isolates of methicillin resistant and methicillin sensitive S.aureus from the Oslo area. ACTA ACUST UNITED AC 2007; 39:1059-62. [PMID: 17852934 DOI: 10.1080/00365540701466231] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Our study compared the susceptibility of 136 clinical isolates of Staphylococcus aureus and 119 multidrug-resistant Staphylococcus aureus (MRSA) isolates from Oslo to a range of antibiotics, including the novel antibiotics quinupristin-dalfopristin, linezolid and daptomycin. All isolates were susceptible to daptomycin, linezolid and quinupristin-dalfopristin, although a subgroup was less susceptible to the latter. There was no linkage between reduced susceptibility to daptomycin, linezolid or quinupristin-dalfopristin and resistance to other classes of antimicrobials. In addition, MRSA strains from 2004 have become more sensitive to fucidin and rifampicin. The results can be used to evaluate the appropriateness of breakpoints and to define a baseline for monitoring possible future emergence of resistance to daptomycin, quinupristin-dalfopristin and linezolid in Staphylococcus aureus in Norway.
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Enoch DA, Bygott JM, Daly ML, Karas JA. Daptomycin. J Infect 2007; 55:205-13. [PMID: 17629567 DOI: 10.1016/j.jinf.2007.05.180] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2007] [Revised: 05/24/2007] [Accepted: 05/25/2007] [Indexed: 12/17/2022]
Abstract
There has been a steady rise in the prevalence of resistant Gram-positive pathogens and concerns about the clinical effectiveness of glycopeptides in treating infections due to Staphylococcus aureus. Daptomycin is a novel lipopeptide antimicrobial agent with activity against Gram-positive organisms, including multi-resistant strains. It is licensed in the USA and Europe for the treatment of complicated skin and soft tissue infections caused by Gram-positive organisms at a dose of 4mg/kg once daily. It has also been licensed in the USA for the treatment of S. aureus bacteraemia and right-sided endocarditis at 6mg/kg once daily. It is a safe and well-tolerated antibiotic, particularly at the current dosing regimen. Antimicrobial resistance, whilst being increasingly reported, still remains relatively rare. Further studies are required to determine the role of daptomycin for the treatment of osteomyelitis and septic arthritis, as well as its use in combination therapy.
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Affiliation(s)
- David A Enoch
- Clinical Microbiology and Public Health Laboratory, Health Protection Agency East of England, Papworth Hospital, Papworth Everard, Cambridgeshire, UK
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20
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Sader HS, Watters AA, Fritsche TR, Jones RN. Daptomycin antimicrobial activity tested against methicillin-resistant staphylococci and vancomycin-resistant enterococci isolated in European medical centers (2005). BMC Infect Dis 2007; 7:29. [PMID: 17442104 PMCID: PMC1865382 DOI: 10.1186/1471-2334-7-29] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2006] [Accepted: 04/18/2007] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Daptomycin is a cyclic lipopeptide with potent activity and broad spectrum against Gram-positive bacteria currently used for the treatment of complicated skin and skin structure infections and bacteremia, including right sided endocarditis. We evaluated the in vitro activity of this compound and selected comparator agents tested against clinical strains of staphylococci and enterococci collected in European medical centers in 2005. METHODS A total of 4,640 strains from 23 medical centers located in 10 European countries, Turkey and Israel (SENTRY Program platform) were tested for susceptibility by reference broth microdilution methods according to Clinical and Laboratory Standards Institute guidelines and interpretative criteria. Mueller-Hinton broth was supplemented to 50 mg/L Ca++ for testing daptomycin. Results for oxacillin (methicillin)-resistant staphylococci and vancomycin-resistant enterococci were analyzed separately. RESULTS Oxacillin resistance rates among Staphylococcus aureus varied from 2.1% in Sweden to 42.5% in the United Kingdom (UK) and 54.7% in Ireland (29.1% overall), while vancomycin resistance rates varied from 0.0% in France, Sweden and Switzerland to 66.7% in the UK and 71.4% in Ireland among Enterococcus faecium (17.9% overall). All S. aureus strains were inhibited at daptomycin MIC of 1 mg/L (MIC50/90, 0.25/0.5 mg/L; 100.0% susceptible) and only one coagulase-negative staphylococci strain (0.1%) showed an elevated (>1 mg/L) daptomycin MIC value (4 mg/L). Among E. faecalis (MIC50/90, 0.5/1 mg/L; 100% susceptible) the highest daptomycin MIC value was 2 mg/L; while among E. faecium (MIC50/90, 2/4 mg/L; 100% susceptible) the highest MIC result was 4 mg/L. CONCLUSION Daptomycin showed excellent in vitro activity against staphylococci and enterococci collected in European medical centers in 2005 and resistance to oxacillin, vancomycin or quinupristin/dalfopristin did not compromise its activity overall against these pathogens. Based on these results and those of previous publications, daptomycin appears to be an excellent therapeutic option for serious infections caused by oxacillin-resistant staphylococci and vancomycin-resistant enterococci in Europe.
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Affiliation(s)
- Helio S Sader
- JMI Laboratories, North Liberty, Iowa, USA
- Universidade Federal de Sao Paulo, Sao Paulo, Brazil
| | | | | | - Ronald N Jones
- JMI Laboratories, North Liberty, Iowa, USA
- Tufts University School of Medicine, Boston, Massachusetts, USA
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21
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Drew RH. Emerging Options for Treatment of Invasive, Multidrug-ResistantStaphylococcus aureusInfections. Pharmacotherapy 2007; 27:227-49. [PMID: 17253914 DOI: 10.1592/phco.27.2.227] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Limited established treatment options exist for the treatment of serious, invasive infections caused by multidrug-resistant Staphylococcus aureus, most notably nosocomially acquired methicillin-resistant S. aureus (MRSA). Although vancomycin represents the gold standard for therapy of such invasive infections, reports of increasing in vitro resistance to vancomycin, combined with reports of clinical failures (with this and other antistaphylococcal agents), underscore the need for alternative therapies. Older agents with favorable in vitro activity available in both oral and intravenous dose forms include trimethoprim-sulfamethoxazole and clindamycin. Limited clinical data exist to support their routine use as initial therapy in the treatment of invasive disease. However, these and other options (e.g., tetracyclines) are being reexplored in the setting of increasing concern over MRSA acquired in the community setting. Newer treatment options for MRSA include linezolid, quinupristin-dalfopristin, daptomycin, and tigecycline. With the exception of linezolid, these newer agents require intravenous administration. Combination therapy may be considered in select invasive diseases refractory to standard monotherapies. These diseases include infections such as endocarditis, meningitis, and prosthetic device infections. Additional alternatives to vancomycin are under clinical investigation. Those in later stages of development include oritavancin, dalbavancin, telavancin, and ceftobiprole.
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Affiliation(s)
- Richard H Drew
- Duke University School of Medicine, Durham, North Carolina, USA.
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Abstract
BACKGROUND Skin and soft tissue infections (SSTIs) and complicated SSTIs (cSSTIs), particularly those caused by Gram-positive pathogens, are among the most common human bacterial infections. The emergence of resistance to antibiotics such as methicillin and vancomycin has compromised treatment options for these infections and stimulated the search for new antimicrobial therapies. Daptomycin, the first in a class of agents known as cyclic lipopeptides, is a novel antibiotic with potent activity against most Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus. SCOPE This review examines the novel properties of daptomycin and describes its therapeutic efficacy and tolerability, particularly in the treatment of cSSTIs. The data search strategy included identification of original research papers, review articles, meeting reports and editorials by searches of MEDLINE and references from relevant articles. FINDINGS In vitro studies have demonstrated that daptomycin has superior bactericidal activity compared with vancomycin and the newer anti-Gram-positive agents, quinupristin/dalfopristin and linezolid. Robust, randomised, phase III clinical trials have shown daptomycin to be effective and well tolerated for the treatment of cSSTIs caused by Gram-positive bacteria, with equivalent clinical success rates and a similar safety profile to those of comparator agents. Data from these studies suggest a trend toward shorter duration of therapy and faster resolution of symptoms with daptomycin. CONCLUSIONS Given the pressing need for new antibiotics to combat infections caused by Gram-positive organisms, and to overcome the problem of resistance to conventional antibiotics, daptomycin is a welcome addition to the treatment options for the management of cSSTIs.
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Affiliation(s)
- Javier Garau
- Hospital Mutua de Terrassa, University of Barcelona, Spain.
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23
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Cilli F, Aydemir S, Tunger A. In vitro activity of daptomycin alone and in combination with various antimicrobials against Gram-positive cocci. J Chemother 2006; 18:27-32. [PMID: 16572890 DOI: 10.1179/joc.2006.18.1.27] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
The increasing prevalence of resistant Gram-positive cocci requires the need to search for more effective agents and synergistic combinations. Forty-two vancomycin-resistant Enterococcus faecium (VREF), 30 methicillin-resistant Staphylococcus aureus (MRSA) and 36 Staphylococcus epidermidis (MRSE) strains were studied. Minimum inhibitory concentrations (MICs) were determined and synergy testing was performed by using E test for daptomycin, ampicillin-sulbactam, piperacillin-tazobactam and ticarcillin-clavulanate against staphylococci; for daptomycin, ampicillin, rifampin, and gentamicin against enterococci. Daptomycin in combination with ampicillin, rifampin, and gentamicin was tested against enterococci; daptomycin in combination with ampicillin-sulbactam, piperacillin-tazobactam, and ticarcillin-clavulanate was tested against staphylococci. Interaction categories were defined by the fractional inhibitory concentration (FIC) index. All strains of staphylococci and enterococci were susceptible to daptomycin. All three combinations showed synergy against more than 70% of the MRSA strains. Daptomycin in combination with ampicillin, rifampin, and gentamicin against enterococci showed synergies of 64.2%, 57.1% and 21.4%, respectively. This study indicates that daptomycin alone and combined with beta-lactams seems to be effective against MRSA, but further in vitro and in vivo studies on the subject are required before clinical use can be recommended.
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Affiliation(s)
- F Cilli
- Ege University Medical School Department of Clinical Microbiology, Izmir, Turkey.
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Sader HS, Fritsche TR, Streit JM, Jones RN. Daptomycin in vitro activity tested against Gram-positive strains collected from European and Latin American medical centers in 2003. J Chemother 2006; 17:477-83. [PMID: 16323435 DOI: 10.1179/joc.2005.17.5.477] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Daptomycin, a cyclic lipopeptide, was susceptibility tested against clinical bacterial isolates consecutively collected in hospitals located in Europe (4,731 strains) and Latin America (1,007 strains) in 2003 as part of a continuing surveillance program. The bacterial isolates tested were Gram-positive pathogens that included staphylococci, streptococci and enterococci. The isolates were tested for susceptibility using broth microdilution methods (broth with 50 mg/L Ca++ for testing daptomycin). All isolates, except two Enterococcus faecium strains from Europe, were inhibited at daptomycin MIC of < or = 4 mg/L. In addition, 99.4 and 97.3% of isolates were inhibited at daptomycin MIC of < or = 2 and < or = 1 mg/L, respectively. Except for one Staphylococcus aureus and one viridans group streptococci from Europe and one coagulase-negative staphylococci from Latin America, all staphylococcal and streptococcal isolates were inhibited by 1 mg/L of daptomycin. Resistance to other compounds (vancomycin, oxacillin, and penicillin) did not influence daptomycin activity. The activity of daptomycin was very similar in both geographic regions evaluated and demonstrated the same MIC distribution as isolates evaluated in studies in the United States. The results of this study showed that daptomycin continues to be very active against clinical isolates of Gram-positive cocci isolated in Europe and Latin America.
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Affiliation(s)
- H S Sader
- JMI Laboratories, North Liberty, Iowa 52317, USA.
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Hsueh PR, Chen WH, Teng LJ, Luh KT. Nosocomial infections due to methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci at a university hospital in Taiwan from 1991 to 2003: resistance trends, antibiotic usage and in vitro activities of newer antimicrobial agents. Int J Antimicrob Agents 2005; 26:43-9. [PMID: 15975769 PMCID: PMC7126964 DOI: 10.1016/j.ijantimicag.2005.04.007] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2005] [Accepted: 04/06/2005] [Indexed: 11/10/2022]
Abstract
A rapid increase of nosocomial methicillin-resistant Staphylococcus aureus (MRSA) infection (from 39% in 1991 to 75% in 2003) and vancomycin-resistant enterococci (VRE) (from 1.2% in 1996 to 6.1% in 2003) at a university hospital in Taiwan was found. The noticeable rise of MRSA and VRE was significantly correlated with the increased consumption of glycopeptides, β-lactam–β-lactamase inhibitor combinations, extended-spectrum cephalosporins, carbapenems and fluoroquinolones (Pearson's correlation coefficient, P < 0.05). Minimum inhibitory concentrations (MICs) of 100 non-duplicate blood isolates of MRSA (in 2003) and of 25 non-duplicate isolates of vancomycin-resistant Enterococcus faecalis and 172 vancomycin-resistant Enterococcus faecium (in 1996–2003) causing nosocomial infection recovered from various clinical specimens of patients treated at the hospital to nine antimicrobial agents were determined by the agar dilution method. All of these isolates were susceptible to linezolid and were inhibited by 0.5 mg/L of tigecycline, and all MRSA isolates were inhibited by daptomycin 1 mg/L, including two isolates of MRSA with heteroresistance to vancomycin. Daptomycin had two-fold better activity against vancomycin-resistant E. faecalis (MIC90, 2 mg/L) than against vancomycin-resistant E. faecium (MIC90, 4 mg/L). Decreased susceptibilities of vancomycin-resistant E. faecium and MRSA to quinupristin/dalfopristin (non-susceptibility 25% and 8%, respectively) were found. Telithromycin had poor activity against the isolates tested (MIC90, 8 mg/L). Linezolid, daptomycin and tigecycline may represent therapeutic options for infections caused by these resistant Gram-positive organisms.
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Affiliation(s)
- Po-Ren Hsueh
- Department of Laboratory Medicine, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, Taiwan.
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Steenbergen JN, Alder J, Thorne GM, Tally FP. Daptomycin: a lipopeptide antibiotic for the treatment of serious Gram-positive infections. J Antimicrob Chemother 2005; 55:283-8. [PMID: 15705644 DOI: 10.1093/jac/dkh546] [Citation(s) in RCA: 386] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Infections caused by drug-resistant pathogens are on the rise. Daptomycin, a cyclic lipopeptide with activity against most Gram-positive pathogens, including vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus, is a newly US-FDA approved antimicrobial for complicated skin and skin structure infections (cSSSI). Daptomycin has a unique mechanism of action that results in destruction of the membrane potential. The rapid bactericidal activity of daptomycin makes it an attractive antibiotic for serious Gram-positive infections.
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