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Robson C, Tan B, Stuart R, Nicholls S, Rogers BA, Sandaradura I. A systematic review of optimal pharmacokinetic/pharmacodynamic parameters for beta-lactam therapy in infective endocarditis. J Antimicrob Chemother 2023; 78:599-612. [PMID: 36691839 DOI: 10.1093/jac/dkad005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 01/02/2023] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND Beta-lactam antibiotics are the mainstay of therapy for most bacterial causes of infective endocarditis (IE). Traditionally considered as agents with a broad therapeutic index, there is increasing recognition that standard doses may be subtherapeutic or toxic in critically ill patients. Optimizing therapy for efficacy requires a defined pharmacokinetic (PK)/pharmacodynamic (PD) target associated with clinical and microbiological cure. OBJECTIVES To elucidate the factors that influence beta-lactam PK and PD variability in IE and to examine optimal PK/PD target parameters for therapy. METHODS The review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Clinical and laboratory in vivo animal or human studies examining PK and/or PD of beta-lactam antibiotics in IE were eligible. Ovid MEDLINE, Embase and Cochrane Central Registry were searched using defined terms. The Office of Health Assessment and Translation (OHAT) tool was used for assessing risk of bias. RESULTS From 2677 abstracts, 62 articles were selected for review and synthesis, comprising: 45 animal studies investigating the broad categories of beta-lactam diffusion into vegetations, PK/PD determinants of outcome, mode of antibiotic delivery and synergistic impact of agents; and 17 human studies totalling 347 participants. Findings supported the importance of time-dependent killing for beta-lactams but heterogeneous data limited the determination of an optimal PK/PD target for IE treatment. CONCLUSION Beta-lactam PK and PD in endocarditis are variable and specific to the particular antibiotic-organism combination. Time-dependent killing is important, consistent with non-endocarditis studies, but there is little agreement on optimal drug exposure. Clinical studies examining PK/PD targets in endocarditis are required to further inform drug selection and dosing.
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Affiliation(s)
- Christopher Robson
- Monash Infectious Diseases, Monash Health, Clayton, VIC, Australia
- Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia
| | - Bryan Tan
- Monash Infectious Diseases, Monash Health, Clayton, VIC, Australia
| | - Rhonda Stuart
- Monash Infectious Diseases, Monash Health, Clayton, VIC, Australia
- Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia
- South Eastern Public Health Unit, Monash Health, Clayton, VIC, Australia
| | - Stephen Nicholls
- Monash Heart, Monash Health, Clayton, VIC, Australia
- Victorian Heart Institute, Monash University, Clayton, VIC, Australia
| | - Benjamin A Rogers
- Monash Infectious Diseases, Monash Health, Clayton, VIC, Australia
- Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia
| | - Indy Sandaradura
- Centre for Infectious Diseases and Microbiology, Westmead Hospital, Sydney, Australia
- School of Medicine, University of Sydney, Sydney, Australia
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Guo S, He Y, Zhu Y, Tang Y, Yu B. Combatting Antibiotic Resistance Using Supramolecular Assemblies. Pharmaceuticals (Basel) 2022; 15:ph15070804. [PMID: 35890105 PMCID: PMC9322166 DOI: 10.3390/ph15070804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 06/18/2022] [Accepted: 06/22/2022] [Indexed: 02/01/2023] Open
Abstract
Antibiotic resistance has posed a great threat to human health. The emergence of antibiotic resistance has always outpaced the development of new antibiotics, and the investment in the development of new antibiotics is diminishing. Supramolecular self-assembly of the conventional antibacterial agents has been proved to be a promising and versatile strategy to tackle the serious problem of antibiotic resistance. In this review, the recent development of antibacterial agents based on supramolecular self-assembly strategies will be introduced.
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Affiliation(s)
- Shuwen Guo
- Key Laboratory of Analytical Chemistry for Life Science of Shaanxi Province, School of Chemistry and Chemical Engineering, Shaanxi Normal University, Xi’an 710100, China;
- Correspondence: (S.G.); (Y.T.); (B.Y.)
| | - Yuling He
- Institute of Basic and Translational Medicine, Xi’an Medical University, No. 1 Xinwang Road, Xi’an 710021, China;
| | - Yuanyuan Zhu
- Key Laboratory of Analytical Chemistry for Life Science of Shaanxi Province, School of Chemistry and Chemical Engineering, Shaanxi Normal University, Xi’an 710100, China;
| | - Yanli Tang
- Key Laboratory of Analytical Chemistry for Life Science of Shaanxi Province, School of Chemistry and Chemical Engineering, Shaanxi Normal University, Xi’an 710100, China;
- Correspondence: (S.G.); (Y.T.); (B.Y.)
| | - Bingran Yu
- State Key Laboratory of Chemical Resource Engineering, Key Lab of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology, Ministry of Education), Beijing 100029, China
- Correspondence: (S.G.); (Y.T.); (B.Y.)
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Turner J, Muraoka A, Bedenbaugh M, Childress B, Pernot L, Wiencek M, Peterson YK. The Chemical Relationship Among Beta-Lactam Antibiotics and Potential Impacts on Reactivity and Decomposition. Front Microbiol 2022; 13:807955. [PMID: 35401470 PMCID: PMC8988990 DOI: 10.3389/fmicb.2022.807955] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 02/14/2022] [Indexed: 12/05/2022] Open
Abstract
Beta-lactam antibiotics remain one of the most commonly prescribed drug classes, but they are limited by their propensity to cause hypersensitivity reactions (e.g., from allergy to anaphylaxis) as well as by the emergence of bacteria with a myriad of resistance mechanisms such as β-lactamases. While development efforts continue to focus on overcoming resistance, there are ongoing concerns regarding cross-contamination of β-lactams during manufacturing and compounding of these drugs. Additionally, there is a need to reduce levels of drugs such as β-lactam antibiotics in waste-water to mitigate the risk of environmental exposure. To help address future development of effective remediation chemistries and processes, it is desired to better understand the structural relationship among the most common β-lactams. This study includes the creation of a class-wide structural ordering of the entire β-lactam series, including both United States Food and Drug Association (US-FDA)-approved drugs and experimental therapies. The result is a structural relational map: the "Lactamome," which positions each substance according to architecture and chemical end-group. We utilized a novel method to compare the structural relationships of β-lactam antibiotics among the radial cladogram and describe the positioning with respect to efficacy, resistance to hydrolysis, reported hypersensitivity, and Woodward height. The resulting classification scheme may help with the development of broad-spectrum treatments that reduce the risk of occupational exposure and negative environmental impacts, assist practitioners with avoiding adverse patient reactions, and help direct future drug research.
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Affiliation(s)
- Jonathan Turner
- College of Medicine, Medical University of South Carolina, Charleston, SC, United States
- College of Pharmacy, Medical University of South Carolina, Charleston, SC, United States
| | - Alyssa Muraoka
- College of Pharmacy, Medical University of South Carolina, Charleston, SC, United States
| | | | - Blaine Childress
- South Carolina Research Authority, Greenville, SC, United States
| | | | | | - Yuri K. Peterson
- College of Pharmacy, Medical University of South Carolina, Charleston, SC, United States
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Lupia T, Pallotto C, Corcione S, Boglione L, De Rosa FG. Ceftobiprole Perspective: Current and Potential Future Indications. Antibiotics (Basel) 2021; 10:170. [PMID: 33567771 PMCID: PMC7915564 DOI: 10.3390/antibiotics10020170] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/19/2021] [Accepted: 01/29/2021] [Indexed: 02/07/2023] Open
Abstract
Ceftobiprole combines an excellent spectrum for community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP) pathogens, with a low/medium MDR risk, and the β-lactams' safety in frail patients admitted to the hospital in internal medicine wards which may be at high risk of adverse events by anti-MRSA coverage as oxazolidinones or glycopeptides. We aimed to report the available evidence regarding ceftobiprole use in pneumonia and invasive bacterial infections, shedding light on ceftobiprole stewardship. The clinical application and real-life experiences of using ceftobiprole for bloodstream infections, including infective endocarditis, are limited but nevertheless promising. In addition, extended-spectrum ceftobiprole activity, including Enterococcus faecalis, Enterobacteriaceae, and Pseudomonas aeruginosa, has theoretical advantages for use as empirical therapy in bacteremia potentially caused by a broad spectrum of microorganisms, such as catheter-related bacteremia. In the future, the desirable approach to sepsis and severe infections will be administered to patients according to their clinical situation, the intrinsic host characteristics, the susceptibility profile, and local epidemiology, while the "universal antibiotic strategy" will no longer be adequate.
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Affiliation(s)
- Tommaso Lupia
- Infectious Diseases Unit, Cardinal Massaia Hospital, 14100 Asti, Italy;
| | - Carlo Pallotto
- Infectious Diseases Unit 1, Santa Maria Annunziata Hospital, Central District, Tuscany Health Care, Bagno a Ripoli, 500012 Florence, Italy;
| | - Silvia Corcione
- Department of Medical Sciences, Infectious Diseases, University of Turin, 10124 Turin, Italy;
- Infectious Diseases, Tufts University School of Medicine, Boston, MA 02109, USA
| | - Lucio Boglione
- Department of Translational Medicine, University of Eastern Piedmont, 28100 Novara, Italy;
| | - Francesco Giuseppe De Rosa
- Infectious Diseases Unit, Cardinal Massaia Hospital, 14100 Asti, Italy;
- Department of Medical Sciences, Infectious Diseases, University of Turin, 10124 Turin, Italy;
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Ceftobripole: Experience in staphylococcal bacteremia. REVISTA ESPANOLA DE QUIMIOTERAPIA : PUBLICACION OFICIAL DE LA SOCIEDAD ESPANOLA DE QUIMIOTERAPIA 2019; 32 Suppl 3:24-28. [PMID: 31364338 PMCID: PMC6755346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Ceftobiprole is a new cephalosporin with an extended spectrum activity against the majority of microorganisms isolated in bacteremia including methicillin-susceptible (MSSA) and -resistant S. aureus (MRSA). This antibiotic has demonstrated a potent activity against MRSA in animal models of endocarditis in monotherapy but particularly in combination with daptomycin, suggesting that this combination could be a future option to improve the outcome of staphylococcal endovascular infections. In addition, the extended-spectrum ceftobiprole activity, including coagulase-negative staphylococci, Enterococcus faecalis, Enterobacteriaceae and Pseudomonas aeruginosa represents an advantage for use as empirical therapy in bacteremia potentially caused by a broad spectrum of microorganisms, such as in catheter-related bacteremia.
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Miragaia M. Factors Contributing to the Evolution of mecA-Mediated β-lactam Resistance in Staphylococci: Update and New Insights From Whole Genome Sequencing (WGS). Front Microbiol 2018; 9:2723. [PMID: 30483235 PMCID: PMC6243372 DOI: 10.3389/fmicb.2018.02723] [Citation(s) in RCA: 94] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Accepted: 10/24/2018] [Indexed: 12/22/2022] Open
Abstract
The understanding of the mechanisms of antibiotic resistance development are fundamental to alert and preview beforehand, the large scale dissemination of resistance to antibiotics, enabling the design of strategies to prevent its spread. The mecA-mediated methicillin resistance conferring resistance to broad-spectrum β-lactams is globally spread in staphylococci including hospitals, farms and community environments, turning ineffective the most widely used and efficient class of antibiotics to treat staphylococcal infections. The use of whole genome sequencing (WGS) technologies at a bacterial population level has provided a considerable progress in the identification of key steps that led to mecA-mediated β-lactam resistance development and dissemination. Data obtained from multiple studies indicated that mecA developed from a harmless core gene (mecA1) encoding the penicillin-binding protein D (PbpD) from staphylococcal species of animal origin (S. sciuri group) due to extensive β-lactams use in human created environments. Emergence of the resistance determinant involved distortion of PbpD active site, increase in mecA1 expression, addition of regulators (mecR1, mecI) and integration into a mobile genetic element (SCCmec). SCCmec was then transferred into species of coagulase-negative staphylococci (CoNS) that are able to colonize both animals and humans and subsequently transferred to S. aureus of human origin. Adaptation of S. aureus to the exogenously acquired SCCmec involved, deletion and mutation of genes implicated in general metabolism (auxiliary genes) and general stress response and the adjustment of metabolic networks, what was accompanied by an increase in β-lactams minimal inhibitory concentration and the transition from a heterogeneous to homogeneous resistance profile. Nowadays, methicillin-resistant S. aureus (MRSA) carrying SCCmec constitutes one of the most important worldwide pandemics. The stages of development of mecA-mediated β-lactam resistance described here may serve as a model for previewing and preventing the emergence of resistance to other classes of antibiotics.
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Affiliation(s)
- Maria Miragaia
- Laboratory of Bacterial Evolution and Molecular Epidemiology, Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal
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Activity of ceftobiprole against Staphylococcus spec. isolates derived from foreign body associated infections. Diagn Microbiol Infect Dis 2018; 91:175-178. [DOI: 10.1016/j.diagmicrobio.2018.01.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Revised: 11/23/2017] [Accepted: 01/11/2018] [Indexed: 11/17/2022]
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Singh KV, Tran TT, Nannini EC, Tam VH, Arias CA, Murray BE. Efficacy of Ceftaroline against Methicillin-Susceptible Staphylococcus aureus Exhibiting the Cefazolin High-Inoculum Effect in a Rat Model of Endocarditis. Antimicrob Agents Chemother 2017; 61:e00324-17. [PMID: 28483961 PMCID: PMC5487651 DOI: 10.1128/aac.00324-17] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Accepted: 05/04/2017] [Indexed: 12/16/2022] Open
Abstract
Certain Staphylococcus aureus strains exhibit an inoculum effect (InE) with cefazolin (CFZ) that has been associated with therapeutic failures in high-inoculum infections. We assessed the in vitro activities of ceftaroline (CPT), CFZ, and nafcillin (NAF) against 17 type A β-lactamase (βla)-producing, methicillin-susceptible S. aureus (MSSA) strains, including the previously reported TX0117, which exhibits the CFZ InE, and its βla-cured derivative, TX0117c. Additionally, we determined the pharmacokinetics of CPT in rats after single intramuscular doses of 20 and 40 mg/kg of body weight and evaluated the activities of CPT (40 mg/kg every 8 h [q8h]), CFZ, and NAF against TX0117 and TX0117c in a rat model of infective endocarditis. No InE was observed for CPT or NAF, whereas a marked InE was detected for CFZ (MIC, 8 to ≥128 μg/ml). CPT and NAF treatment against TX0117 resulted in mean bacterial counts of 2.3 and 2.1 log10 CFU/g in vegetations, respectively, compared to a mean of 5.9 log10 CFU/g in the CFZ-treated group (CPT and NAF versus CFZ, P = 0.001; CPT versus NAF, P = 0.9830). Both CFZ and CPT were efficacious against the βla-cured derivative, TX0117c, compared to time zero (t0) (P = <0.0001 and 0.0015, respectively). Our data reiterate the in vivo consequences of the CFZ InE and show that CPT is not affected by this phenomenon. CPT might be considered for high-inoculum infections caused by MSSA exhibiting the CFZ InE.
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Affiliation(s)
- Kavindra V Singh
- Division of Infectious Diseases, Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA
- Center for Antimicrobial Resistance and Microbial Genomics, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), Houston, Texas, USA
| | - Truc T Tran
- Division of Infectious Diseases, Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA
- Center for Antimicrobial Resistance and Microbial Genomics, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), Houston, Texas, USA
| | - Esteban C Nannini
- Division of Infectious Diseases, School of Medicine, Universidad Nacional de Rosario,. Instituto de Inmunología Clínica y Experimental Rosario (IDICER), CONICET, Rosario, Argentina
| | - Vincent H Tam
- College of Pharmacy, University of Houston, Houston, Texas, USA
| | - Cesar A Arias
- Division of Infectious Diseases, Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA
- Department of Microbiology and Molecular Genetics, University of Texas Medical School at Houston, Houston, Texas, USA
- Molecular Genetics and Antimicrobial Resistance Unit, Universidad El Bosque, Bogota, Colombia
- Center for Antimicrobial Resistance and Microbial Genomics, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), Houston, Texas, USA
| | - Barbara E Murray
- Division of Infectious Diseases, Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA
- Department of Microbiology and Molecular Genetics, University of Texas Medical School at Houston, Houston, Texas, USA
- Center for Antimicrobial Resistance and Microbial Genomics, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), Houston, Texas, USA
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Efficacy of Telavancin Alone and in Combination with Ampicillin in a Rat Model of Enterococcus faecalis Endocarditis. Antimicrob Agents Chemother 2017; 61:AAC.02489-16. [PMID: 28320712 DOI: 10.1128/aac.02489-16] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Accepted: 03/06/2017] [Indexed: 11/20/2022] Open
Abstract
We first assessed telavancin (TLV) pharmacokinetics in rats after a single subcutaneous dose of 35 mg/kg of body weight. The pharmacokinetic data were used to predict a TLV dose that simulates human exposure, and the efficacy of TLV was then evaluated using a TLV dose of 21 mg/kg every 12 h against Enterococcus faecalis OG1RF (TLV MIC of 0.06 μg/ml) in a rat endocarditis model with an indwelling catheter. Therapy was given for 3 days with TLV, daptomycin (DAP), or ampicillin (AMP) monotherapy and with combinations of TLV plus AMP, AMP plus gentamicin (GEN), and AMP plus ceftriaxone (CRO); rats were sacrificed 24 h after the last dose. Antibiotics were given to simulate clinically relevant concentrations or as used in other studies. TLV treatment resulted in a significant decrease in bacterial burden (CFU per gram) in vegetations from 6.0 log10 at time 0 to 3.1 log10 after 3 days of therapy. Bacterial burdens in vegetations were also significantly lower in the TLV-treated rats than in the AMP (P = 0.0009)- and AMP-plus-GEN (P = 0.035)-treated rats but were not significantly different from that of the AMP-plus-CRO-treated rats. Bacterial burdens from vegetations in TLV monotherapy and TLV-plus-AMP-and-DAP groups were similar to each other (P ≥ 0.05). Our data suggest that further study of TLV as a therapeutic alternative for deep-seated infections caused by vancomycin-susceptible E. faecalis is warranted.
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Abstract
PURPOSE We compared the resistance patterns of methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-susceptible Staphylococcus aureus (MSSA) keratitis isolates with the common topically applied ophthalmic antimicrobials. METHODS We reviewed the antibiotic susceptibility results of 122 MRSA and 276 MSSA keratitis isolates from January 1993 to November 2012. In vitro susceptibility testing of each Staphylococcus aureus (SA) isolate was performed using Kirby-Bauer disk diffusion based on modified serum interpretations for cefoxitin, bacitracin, cefazolin, ciprofloxacin, gatifloxacin, gentamicin, moxifloxacin, ofloxacin, polymyxin B, sulfamethoxazole, tobramycin, and trimethoprim. RESULTS MRSA represented 30.7% (122 of 398) of the total SA isolates. All the SA isolates were susceptible to vancomycin, whereas they were less susceptible to the fluoroquinolones than to the non-fluoroquinolones. In comparison with MSSA, MRSA was significantly more resistant to all the antibiotics tested other than polymyxin B (both equally resistant) and vancomycin (both equally susceptible) (P < 0.001). Besides vancomycin, MRSA demonstrated the best susceptibilities to sulfamethoxazole (94.3%), bacitracin (89.3%), trimethoprim (88.5%), and gentamicin (86.1%). Additionally, MRSA was found to be significantly more resistant to the second-generation fluoroquinolones (ciprofloxacin and ofloxacin) than to the fourth-generation fluoroquinolones (moxifloxacin and gatifloxacin). An increase in resistance to the fourth-generation fluoroquinolones was detected for both MRSA and MSSA over the study period. CONCLUSIONS The in vitro susceptibilities of commonly used topical antibiotics differ for MRSA and MSSA isolates; thus, successful treatment of bacterial keratitis should be supported with laboratory studies. Vancomycin remains the treatment of choice for MRSA keratitis. The empiric use of second-generation fluoroquinolones seems to be contraindicated in the treatment of MRSA keratitis.
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Morales-Cartagena A, Lalueza A, López-Medrano F, Juan RS, Aguado JM. Treatment of methicillin-resistant Staphylococcus aureus infections: Importance of high vancomycin minumum inhibitory concentrations. World J Clin Infect Dis 2015; 5:14-29. [DOI: 10.5495/wjcid.v5.i2.14] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2014] [Revised: 10/30/2014] [Accepted: 03/09/2015] [Indexed: 02/06/2023] Open
Abstract
Staphylococcus aureus (SA) infections remain a major cause of morbidity and mortality despite the availability of numerous effective anti-staphylococcal antibiotics. This organism is responsible for both nosocomial and community-acquired infections ranging from relatively minor skin and soft tissue infections to life-threatening systemic infections. The increasing incidence of methicillin-resistant strains has granted an increasing use of vancomycin causing a covert progressive increase of its minimum inhibitory concentration (MIC) (dubbed the MIC “creep”). In this way, the emergence of vancomycin-intermediate SA (VISA) strains and heteroresistant-VISA has raised concern for the scarcity of alternative treatment options. Equally alarming, though fortunately less frequent, is the emergence of vancomycin-resistant SA. These strains show different mechanisms of resistance but have similar problems in terms of therapeutic approach. Ultimately, various debate issues have arisen regarding the emergence of SA strains with a minimum inhibitory concentration sitting on the superior limit of the sensitivity range (i.e., MIC = 2 μg/mL). These strains have shown certain resilience to vancomycin and a different clinical behaviour regardless of vancomycin use, both in methicillin-resistant SA and in methicillin-sensitive SA. The aim of this text is to revise the clinical impact and consequences of the emergence of reduced vancomycin susceptibility SA strains, and the different optimal treatment options known.
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Syed YY. Ceftobiprole medocaril: a review of its use in patients with hospital- or community-acquired pneumonia. Drugs 2014; 74:1523-42. [PMID: 25117196 DOI: 10.1007/s40265-014-0273-x] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Ceftobiprole, the active metabolite of the prodrug ceftobiprole medocaril (Zevtera(®)), is a new generation broad-spectrum intravenous cephalosporin with activity against methicillin-resistant Staphylococcus aureus. Ceftobiprole exhibits potent in vitro activity against a number of Gram-positive and Gram-negative pathogens associated with hospital-acquired pneumonia (HAP) and community-acquired pneumonia (CAP). It is the first cephalosporin monotherapy approved in the EU for the treatment of both HAP (excluding ventilator associated-pneumonia [VAP]) and CAP. In phase III trials, ceftobiprole medocaril was noninferior, in terms of clinical cure rates at the test-of-cure visit, to ceftazidime plus linezolid in patients with HAP and to ceftriaxone ± linezolid in patients with CAP severe enough to require hospitalization. In patients with HAP, noninferiority of ceftobiprole medocaril to ceftazidime plus linezolid was not demonstrated in a subset of patients with VAP. In patients with CAP, ceftobiprole medocaril was effective in those at risk for poor outcomes (pneumonia severity index ≥91, Pneumonia Patient Outcomes Research Team score IV-V or bacteraemic pneumonia). In the phase III trials, ceftobiprole medocaril was generally well tolerated, with ≈10 % of patients discontinuing the treatment because of adverse events. The most common treatment-related adverse events occurring in ceftobiprole recipients in the trials in patients with HAP or CAP included nausea, diarrhoea, infusion site reactions, vomiting, hepatic enzyme elevations and hyponatraemia. Therefore, ceftobiprole medocaril monotherapy offers a simplified option for the initial empirical treatment of patients with HAP (excluding VAP) and in those with CAP requiring hospitalization.
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Affiliation(s)
- Yahiya Y Syed
- Springer, Private Bag 65901, Mairangi Bay 0754, Auckland, New Zealand,
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Schirmer PL, Deresinski SC. Ceftobiprole: a new cephalosporin for the treatment of skin and skin structure infections. Expert Rev Anti Infect Ther 2014; 7:777-91. [DOI: 10.1586/eri.09.54] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Ceftobiprole medocaril is an effective treatment against methicillin-resistant Staphylococcus aureus (MRSA) mediastinitis in a rat model. Eur J Clin Microbiol Infect Dis 2013; 33:325-9. [PMID: 24030718 DOI: 10.1007/s10096-013-1959-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2013] [Accepted: 08/12/2013] [Indexed: 10/26/2022]
Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) mediastinitis after median sternotomy is a major complication of cardiac surgery with significant morbidity and mortality rates. We evaluated the efficacy of ceftobiprole medocaril in a new rat model of mediastinitis and compared it to vancomycin. The model was induced in 92 rats. Infection was induced immediately after median sternotomy by the injection of MRSA (strain 3020, 1 × 10(7) cfu/rat) into the sternal bone. After 24 h, rats (groups of 6-8) were treated intraperitoneally for 5 days or 14 days by either: (i) saline (control, q8h), (ii) ceftobiprole medocaril (70 or 100 mg/kg, q8h), or (iii) vancomycin (50 mg/kg, q12h). Efficacy was determined by a reduction in bacterial cfu in the sternum and spleen tissues. Comparisons were performed using the Mann-Whitney test. A 5-day treatment course of ceftobiprole at both doses tested lead to a significant reduction in MRSA load in the sternum (p < 0.01) as compared to the control group and compared to 5-day vancomycin treatment, which lead to a non-significant reduction (p = 0.07). Longer treatment (14 days) with ceftobiprole lead to a complete clearance of MRSA from the sternum, similarly to vancomycin. Ceftobiprole also showed a significant effect on eliminating MRSA dissemination to the spleen compared to saline-treated rats. Ceftobiprole was effective in treating MRSA mediastinitis in the rat model. In the 5-day course, ceftobiprole showed a significant reduction in sternal MRSA counts and was superior to vancomycin. After 14 days, both ceftobiprole and vancomycin showed clearance of MRSA from the sternum in more than 50 % of rats and almost complete clearance in the remainder.
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Ball AP, Bartlett JG, Craig WA, Drusano GL, Felmingham D, Garau JA, Klugman KP, Low DE, Mandell LA, Rubinstein E, Tillotson GS. Future Trends in Antimicrobial Chemotherapy: Expert Opinion on the 43rdICAAC. J Chemother 2013; 16:419-36. [PMID: 15565907 DOI: 10.1179/joc.2004.16.5.419] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
The current document bestows an expert synopsis of key new information presented at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) meeting in 2003. Data is presented on the socio-political aspects of and policies on antimicrobial prescribing, novel mechanisms of resistance in Streptococcus pneumoniae, and current epidemiological trends in global resistance. Novel information on new (and existing) antimicrobial agents--new penicillins, cephalosporins, monobactams and oxipenem inhibitors, ketolides, glycopeptides, fluoroquinolones (and hybrids), peptides, daptomycin, aminomethylcyclines, glycylcyclines, and newer formulations of agents such as amoxycillin-clavulanate--provides renewed hope that resistant pathogens can be controlled through use of more potent agents. Improved strategies for the use of existing antimicrobial agents, such as the use of high-dose regimens, short-course therapy, also may delay or reduce the development of resistance and preserve the value of our antibiotic armamentarium.
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Affiliation(s)
- A P Ball
- University of St Andrews, Fife, Scotland, UK
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In Vivo Effects of Cefazolin, Daptomycin, and Nafcillin in Experimental Endocarditis with a Methicillin-Susceptible Staphylococcus aureus Strain Showing an Inoculum Effect against Cefazolin. Antimicrob Agents Chemother 2013; 57:4276-4281. [PMID: 23796934 DOI: 10.1128/aac.00856-13] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2013] [Accepted: 06/14/2013] [Indexed: 12/11/2022] Open
Abstract
Several reports have implicated the inoculum effect that some strains of type A beta-lactamase (Bla)-producing, methicillin-susceptible Staphylococcus aureus (MSSA) show against cefazolin as the cause for clinical failures in certain serious deep-seated infections. Here, using a previously reported MSSA strain displaying this phenotype (TX0117), we obtained a Bla-cured derivative (TX0117c) with a combination of novobiocin and high temperature. Both isolates were then used in a rat endocarditis model and treated with cefazolin, nafcillin, and daptomycin, given to simulate human dosing. Animals were treated for 3 days and either sacrificed at 24 h after the last antibiotic dose (standard group) or left untreated for an additional 3 days (relapse group). With TX0117 in the standard treatment group, daptomycin and nafcillin were both significantly better than cefazolin in reducing CFU/g of vegetations, achieving mean log10 reductions compared to levels in untreated rats of 7.1, 5.3, and 1.8, respectively (cefazolin versus daptomycin, P < 0.0001; cefazolin versus nafcillin, P = 0.005; daptomycin versus nafcillin, P = 0.053). In addition, cefazolin was significantly more effective in reducing vegetation titers of TX0117c than of TX0117 (mean log10 reduction of 1.4 versus 5.5, respectively; P = 0.0001). Similar results were observed with animals in the relapse group. Thus, these data show that there can be an in vivo consequence of the in vitro inoculum effect that some MSSA strains display against cefazolin and indicate a specific role for Bla production using a Bla-cured derivative strain against which cefazolin regained both in vitro and in vivo activity.
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Deng JZ. Methicillin/per-6-(4-methoxylbenzyl)-amino-6-deoxy-β-cyclodextrin 1:1 complex and its potentiation in vitro against methicillin-resistant Staphylococcus aureus. J Antibiot (Tokyo) 2013; 66:517-21. [DOI: 10.1038/ja.2013.51] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2013] [Revised: 04/11/2013] [Accepted: 04/16/2013] [Indexed: 11/09/2022]
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Alternative Agents to Vancomycin for the Treatment of Methicillin-Resistant Staphylococcus aureus Infections. Am J Ther 2013; 20:200-12. [DOI: 10.1097/mjt.0b013e31821109ec] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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Ceftobiprole efficacy in vitro against Panton-Valentine leukocidin production and in vivo against community-associated methicillin-resistant Staphylococcus aureus osteomyelitis in rabbits. Antimicrob Agents Chemother 2012; 56:6291-7. [PMID: 23027197 DOI: 10.1128/aac.00926-12] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) can cause osteomyelitis with severe sepsis and/or local complications in which a Panton-Valentine leukocidin (PVL) role is suspected. In vitro sub-MIC antibiotic effects on growth and PVL production by 11 PVL(+) MRSA strains, including the major CA-MRSA clones (USA300, including the LAC strain; USA400; and USA1000), and 11 PVL(+) methicillin-susceptible S. aureus (MSSA) strains were tested in microplate culture. Time-kill analyses with ceftobiprole at its MIC were also run with LAC. Efficacies of ceftobiprole (40 mg/kg of body weight subcutaneously [s.c.] four times a day [q.i.d.]) or vancomycin (60 mg/kg intramuscularly [i.m.] twice a day [b.i.d.]) alone or combined with rifampin (10 mg/kg b.i.d.) against rabbit CA-MRSA osteomyelitis, induced by tibial injection of 3.4 × 10(7) CFU of LAC, were compared. Treatment, started 14 days postinoculation, lasted 14 days. In vitro, 6/11 strains cultured with sub-MICs of ceftobiprole produced 1.6- to 4.8-fold more PVL than did the controls, with no link to specific clones. Rifampin decreased PVL production by all tested strains. In time-kill analyses at the LAC MIC (0.75 mg/liter), PVL production rose transiently at 6 and 8 h and then declined 2-fold at 16 h, concomitant with a 2-log(10)-CFU-count decrease. In vivo, the mean log(10) CFU/g of bone for ceftobiprole (1.44 ± 0.40) was significantly lower than that for vancomycin (2.37 ± 1.22) (P = 0.034), with 7/10 versus 5/11 bones sterilized, respectively. Combination with rifampin enhanced ceftobiprole (1.16 ± 0.04 CFU/g of bone [P = 0.056], 11/11 sterile bones) and vancomycin (1.23 ± 0.06 CFU/g [P = 0.011], 11/11 sterile bones) efficacies. Ceftobiprole bactericidal activity and the rifampin anti-PVL effect could play a role in these findings, which should be of interest for treating CA-MRSA osteomyelitis.
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Efficacy of ceftobiprole Medocaril against Enterococcus faecalis in a murine urinary tract infection model. Antimicrob Agents Chemother 2012; 56:3457-60. [PMID: 22450988 DOI: 10.1128/aac.06102-11] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
We evaluated ceftobiprole against the well-characterized Enterococcus faecalis strain OG1RF (with and without the β-lactamase [Bla] plasmid pBEM10) in a murine urinary tract infection (UTI) model. Ceftobiprole was equally effective for Bla(+) and Bla(-) OG1 strains, while ampicillin was moderately to markedly (depending on the inoculum) less effective against Bla(+) than Bla(-) OG1 strains. These data illustrate an in vivo effect on ampicillin of Bla production by E. faecalis and the stability and efficacy of ceftobiprole in experimental UTI.
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Synergistic activity of ceftobiprole and vancomycin in a rat model of infective endocarditis caused by methicillin-resistant and glycopeptide-intermediate Staphylococcus aureus. Antimicrob Agents Chemother 2012; 56:1476-84. [PMID: 22232278 DOI: 10.1128/aac.06057-11] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The therapeutic activity of ceftobiprole medocaril, the prodrug of ceftobiprole, was compared to that of vancomycin, daptomycin, and the combination of a subtherapeutic dose of ceftobiprole and vancomycin in a rat model of infective endocarditis due to methicillin-resistant Staphylococcus aureus (MRSA) (ATCC 43300) or glycopeptide-intermediate Staphylococcus aureus (GISA) (NRS4 and HIP 5836) strains. The minimum bactericidal concentrations of ceftobiprole, vancomycin, and daptomycin at bacterial cell densities similar to those encountered in the cardiac vegetation in the rat endocarditis model were 2, >64, and 8 μg/ml, respectively, for MRSA ATCC 43300 and 4, >64, and 8 μg/ml, respectively, for the GISA strain. Ceftobiprole medocaril administered in doses of 100 mg/kg of body weight given intravenously (i.v.) twice a day (BID) every 8 h (q8h) (equivalent to a human therapeutic dose of ceftobiprole [500 mg given three times a day [TID]) was the most effective monotherapy, eradicating nearly 5 log(10) CFU/g MRSA or 6 log(10) CFU/g GISA organisms from the cardiac vegetation and had the highest incidence of sterile vegetation compared to the other monotherapies in the endocarditis model. In in vitro time-kill studies, synergistic effects were observed with ceftobiprole and vancomycin on MRSA and GISA strains, and in vivo synergy was noted with combinations of subtherapeutic doses of these agents for the same strains. Additionally, sterile vegetations were achieved in 33 and 60%, respectively, of the animals infected with MRSA ATCC 43300 or GISA NRS4 receiving ceftobiprole-vancomycin combination therapy. In summary, ceftobiprole was efficacious both as monotherapy and in combination with vancomycin in treating MRSA and GISA infections in a rat infective endocarditis model and warrants further evaluation.
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Evaluation of ceftobiprole activity against a variety of gram-negative pathogens, including Escherichia coli, Haemophilus influenzae (β-lactamase positive and β-lactamase negative), and Klebsiella pneumoniae, in a rabbit meningitis model. Antimicrob Agents Chemother 2011; 56:921-5. [PMID: 22064544 DOI: 10.1128/aac.01537-10] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Ceftobiprole medocaril, a new cephalosporin, is highly active against a broad spectrum of Gram-positive and Gram-negative clinical pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant pneumococci. In this study, we tested ceftobiprole against various Gram-negative pathogens in a rabbit meningitis model and determined its penetration into the cerebrospinal fluid (CSF). In this animal model, ceftobiprole produced an antibacterial activity similar to that of cefepime against an Escherichia coli strain, a Klebsiella pneumoniae strain, and a β-lactamase-negative Haemophilus influenzae strain. Against a β-lactamase-positive H. influenzae strain, ceftobiprole was significantly superior. The penetration of ceftobiprole through inflamed meninges reached about 16% of serum levels compared to about 2% of serum levels through uninflamed meninges.
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In vivo synergism of ceftobiprole and vancomycin against experimental endocarditis due to vancomycin-intermediate Staphylococcus aureus. Antimicrob Agents Chemother 2011; 55:3977-84. [PMID: 21730114 DOI: 10.1128/aac.00402-11] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The efficacy of ceftobiprole combined with vancomycin was tested against two vancomycin-intermediate Staphylococcus aureus (VISA) strains, PC3 and Mu50, in rats with experimental endocarditis. Animals with infected aortic vegetations were treated for 3 days with doses simulating the kinetics after intravenous administration in humans of (i) the standard dose of ceftobiprole of 500 mg every 12 h (b.i.d.) (SD-ceftobiprole), (ii) a low dose of ceftobiprole of 250 mg b.i.d. (LD-ceftobiprole), (iii) a very low dose of ceftobiprole of 125 mg b.i.d. (VLD-ceftobiprole), (iv) SD-vancomycin of 1 g b.i.d., or (v) LD- or VLD-ceftobiprole combined with SD-vancomycin. Low dosages of ceftobiprole were purposely used to highlight positive drug interactions. Treatment with SD-ceftobiprole sterilized 12 of 14 (86%) and 10 of 13 (77%) vegetations infected with PC3 and Mu50, respectively (P < 0.001 versus controls). In comparison, LD-ceftobiprole sterilized 10 of 11 (91%) vegetations infected with PC3 (P < 0.01 versus controls) but only 3 of 12 (25%) vegetations infected with Mu50 (P > 0.05 versus controls). VLD-ceftobiprole and SD-vancomycin alone were ineffective against both strains (≤8% sterile vegetations). In contrast, the combination of VLD-ceftobiprole and SD-vancomycin sterilized 7 of 9 (78%) and 6 of 14 (43%) vegetations infected with PC3 and Mu50, respectively, and the combination of LD-ceftobiprole and SD-vancomycin sterilized 5 of 6 (83%) vegetations infected with Mu50 (P < 0.05 versus controls and monotherapy). Thus, ceftobiprole monotherapy simulating standard therapeutic doses was active against VISA experimental endocarditis. Moreover, subtherapeutic LD- and VLD-ceftobiprole synergized with ineffective vancomycin to restore efficacy. Hence, combining ceftobiprole with vancomycin broadens the therapeutic margin of these two compounds against VISA infections.
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Microtiter plate-based assay for inhibitors of penicillin-binding protein 2a from methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 2011; 55:2783-7. [PMID: 21402836 DOI: 10.1128/aac.01327-10] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Penicillin-binding protein 2a (PBP2a), the molecular determinant for high-level β-lactam resistance in methicillin-resistant Staphylococcus aureus (MRSA), is intrinsically resistant to most β-lactam antibiotics. The development and characterization of new inhibitors targeting PBP2a would benefit from an effective and convenient assay for inhibitor binding. This study was directed toward the development of a fluorescently detected β-lactam binding assay for PBP2a from MRSA. Biotinylated ampicillin and biotinylated cephalexin were tested as tagging reagents for fluorescence detection by using a streptavidin-horseradish peroxidase conjugate. Both bound surprisingly well to PBP2a, with binding constants of 1.6 ± 0.4 μM and 13.6 ± 0.8 μM, respectively. Two forms of the assay were developed, a one-step direct competition form of the assay and a two-step indirect competition form of the assay, and both forms of the assay gave comparable results. This assay was then used to characterize PBP2a binding to ceftobiprole, which gave results consistent with previous studies of ceftobiprole-PBP2a binding. This assay was also demonstrated for screening for PBP2a inhibitors by screening a set of 13 randomly selected β-lactams for PBP2a inhibition at 750 μM. Meropenem was observed to give substantial inhibition in this screen, and a follow-up titration experiment determined its apparent K(i) to be 480 ± 70 μM. The availability of convenient and sensitive microtiter-plate based assays for the screening and characterization of PBP2a inhibitors is expected to facilitate the discovery and development of new PBP2a inhibitors for use in combating the serious public health problem posed by MRSA.
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Lascols C, Legrand P, Mérens A, Leclercq R, Muller-Serieys C, Drugeon HB, Kitzis MD, Reverdy ME, Roussel-Delvallez M, Moubareck C, Brémont S, Miara A, Gjoklaj M, Soussy CJ. In vitro antibacterial activity of ceftobiprole against clinical isolates from French teaching hospitals: proposition of zone diameter breakpoints. Int J Antimicrob Agents 2011; 37:235-9. [PMID: 21295447 DOI: 10.1016/j.ijantimicag.2010.11.035] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2010] [Revised: 08/03/2010] [Accepted: 11/29/2010] [Indexed: 10/18/2022]
Abstract
The aims of this study were to determine the in vitro activity profile of ceftobiprole, a pyrrolidinone cephalosporin, against a large number of bacterial pathogens and to propose zone diameter breakpoints for clinical categorisation according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) minimum inhibitory concentration (MIC) breakpoints. MICs of ceftobiprole were determined by broth microdilution against 1548 clinical isolates collected in eight French hospitals. Disk diffusion testing was performed using 30 μg disks according to the method of the Comité de l'Antibiogramme de la Société Française de Microbiologie (CA-SFM). The in vitro activity of ceftobiprole, expressed by MIC(50/90) (MICs for 50% and 90% of the organisms, respectively) (mg/L), was as follows: meticillin-susceptible Staphylococcus aureus, 0.25/0.5; meticillin-resistant S. aureus (MRSA), 1/2; meticillin-susceptible coagulase-negative staphylococci (CoNS), 0.12/0.5; meticillin-resistant CoNS, 1/2; penicillin-susceptible Streptococcus pneumoniae, ≤ 0.008/0.03; penicillin-resistant S. pneumoniae, 0.12/0.5; viridans group streptococci, 0.03/0.12; β-haemolytic streptococci, ≤ 0.008/0.016; Enterococcus faecalis, 0.25/1; Enterococcus faecium, 64/128; Enterobacteriaceae, 0.06/32; Pseudomonas aeruginosa, 4/16; Acinetobacter baumannii, 0.5/64; Haemophilus influenzae, 0.03/0.12; and Moraxella catarrhalis, 0.25/0.5. According to the regression curve, zone diameter breakpoints could be 28, 26, 24 and 22 mm for MICs of 0.5, 1, 2 and 4 mg/L respectively. In conclusion, this study confirms the potent in vitro activity of ceftobiprole against many Gram-positive bacteria, including MRSA but not E. faecium, whilst maintaining a Gram-negative spectrum similar to the advanced-generation cephalosporins such as cefepime. Thus ceftobiprole appears to be well suited for the empirical treatment of a variety of healthcare-associated infections.
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Affiliation(s)
- C Lascols
- Service de Bactériologie-Virologie-Hygiène, CHU Henri Mondor, Assistance Publique-Hôpitaux de Paris, Université Paris 12, 94010 Créteil Cedex, France.
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Ceftobiprole: The First Broad-Spectrum Anti–methicillin-resistant Staphylococcus aureus Beta-Lactam. ACTA ACUST UNITED AC 2011. [DOI: 10.1016/j.jecm.2010.12.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Ceftobiprole: A novel, broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus. Am J Health Syst Pharm 2010; 67:983-93. [PMID: 20516468 DOI: 10.2146/ajhp090285] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
PURPOSE The pharmacology, antimicrobial activity, pharmacokinetics, pharmacodynamics, clinical efficacy, safety, and place in therapy of ceftobiprole are reviewed. SUMMARY Ceftobiprole, a novel, broad-spectrum, parenteral cephalosporin, inhibits the cell-wall synthesis of penicillin-binding proteins (PBPs) PBP2a and PBP2x, responsible for the resistance in staphylococci and pneumococci, respectively. Ceftobiprole has good activity against gram-positive aerobes and anaerobes, and its activity against gram-negative aerobes and anaerobes is species dependent. Ceftobiprole is relatively inactive against Acinetobacter species. Its ability to bind relevant PBPs of resistant gram-positive and gram-negative bacteria indicates its potential use in the treatment of hospital-acquired pneumonia and complicated skin and skin-structure infections (cSSSIs). Ceftobiprole is primarily excreted unchanged by the kidneys and exhibits linear pharmacokinetics. The half-life of the drug is approximately 3-4 hours. It exhibits minimal plasma protein binding (16%). Ceftobiprole does not inhibit the cytochrome P-450 isoenzyme system, so the possibility of drug-drug interactions is low. The drug has not been approved for use in the United States but has been approved in Canada and elsewhere. Ceftobiprole is currently undergoing Phase III clinical trials and has demonstrated activity against methicillin-resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae, and Pseudomonas aeruginosa. Completed Phase III trials used i.v. dosages of 500 mg every 8-12 hours. The most commonly observed adverse effects of ceftobiprole included headache and gastrointestinal upset. CONCLUSION Ceftobiprole is a novel, broad-spectrum, parenteral cephalosporin undergoing Phase III clinical trials. Its broad spectrum of activity makes it a candidate for monotherapy of cSSSIs and pneumonias that have required combination therapy in the past.
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Bustos C, Del Pozo JL. Emerging agents to combat complicated and resistant infections: focus on ceftobiprole. Infect Drug Resist 2010; 3:5-14. [PMID: 21694889 PMCID: PMC3108737 DOI: 10.2147/idr.s3681] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2010] [Indexed: 11/23/2022] Open
Abstract
Antimicrobial resistance is a global concern. Over the past few years, considerable efforts and resources have been expended to detect, monitor, and understand at the basic level the many different facets of emerging and increasing resistance. Development of new antimicrobial agents has been matched by the development of new mechanisms of resistance by bacteria. Current antibiotics act at a variety of sites within the target bacteria, including the cross-linking enzymes in the cell wall, various ribosomal enzymes, nucleic acid polymerases, and folate synthesis. Ceftobiprole is a novel parenteral cephalosporin with high affinity for most penicillin-binding proteins, including the mecA product penicillin-binding protein 2a, rendering it active against methicillin-resistant staphylococci. Its in vitro activity against staphylococci and multiresistant pneumococci, combined with its Gram-negative spectrum comparable to that of other extended-spectrum cephalosporins, its stability against a wide range of beta-lactamases, and its pharmacokinetic and safety profiles make ceftobiprole an attractive and well tolerated new antimicrobial agent. The US Food and Drug Administration granted ceftobiprole medocaril fast-track status in 2003 for the treatment of complicated skin infections and skin structure infections due to methicillin-resistant staphylococci, and subsequently extended this to treatment of hospital-acquired pneumonia, including ventilator-associated pneumonia due to suspected or proven methicillin-resistant Staphylococcus aureus.
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Interaction of ceftobiprole with the low-affinity PBP 5 of Enterococcus faecium. Antimicrob Agents Chemother 2009; 54:953-5. [PMID: 19917749 DOI: 10.1128/aac.00983-09] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Ceftobiprole is a new cephalosporin that exhibits a high level of affinity for methicillin-resistant Staphylococcus aureus PBP 2a. It was reported that ceftobiprole did not interact with a mutated form of the low-affinity protein Enterococcus faecium PBP 5 (PBP 5fm) that, when overexpressed, confers a beta-lactam resistance phenotype to the bacterium. Our results show that ceftobiprole binds to unmutated PBP 5fm to form a stable acyl-enzyme and that ceftobiprole is able to efficiently kill a penicillin-resistant Enterococcus faecium strain that produces this protein.
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Ceftobiprole is superior to vancomycin, daptomycin, and linezolid for treatment of experimental endocarditis in rabbits caused by methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 2009; 54:610-3. [PMID: 19917746 DOI: 10.1128/aac.00886-09] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Beta lactam agents are the most active drugs for the treatment of streptococci and methicillin-susceptible Staphylococcus aureus endocarditis. However, methicillin-resistant S. aureus (MRSA) is resistant to all beta lactam agents licensed to date, and alternative treatments are limited. Ceftobiprole is a novel broad-spectrum cephalosporin that binds with high affinity to PBP 2a, the penicillin binding protein that mediates the methicillin resistance of staphylococci and is active against MRSA. Ceftobiprole was compared to vancomycin, daptomycin, and linezolid in a rabbit model of MRSA aortic valve endocarditis caused by the homogeneously methicillin-resistant laboratory strain COL. Residual organisms in vegetations were significantly fewer in ceftobiprole-treated rabbits than in any other treatment group (P<0.05 for each comparison). In addition, the numbers of organisms in spleens and in kidneys were significantly lower in ceftobiprole-treated rabbits than in linezolid- and vancomycin-treated animals (P<0.05 for each comparison). Anti-MRSA beta lactam agents such as ceftobiprole may represent a significant therapeutic advance over currently available agents for the treatment of MRSA endocarditis.
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In vivo activity of ceftobiprole in murine skin infections due to Staphylococcus aureus and Pseudomonas aeruginosa. Antimicrob Agents Chemother 2009; 54:116-25. [PMID: 19884364 DOI: 10.1128/aac.00642-09] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Ceftobiprole, a broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA) (P. Hebeisen et al., Antimicrob. Agents Chemother. 45:825-836, 2001), was evaluated in a subcutaneous skin infection model with Staphylococcus aureus Smith OC 4172 (methicillin-susceptible S. aureus [MSSA]), S. aureus OC 8525 (MRSA), Pseudomonas aeruginosa OC 4351 (having an inducible AmpC beta-lactamase), and P. aeruginosa OC 4354 (overproducing AmpC beta-lactamase). In the MSSA and MRSA infection models, ceftobiprole, administered as the prodrug ceftobiprole medocaril, was more effective in reducing CFU/g skin (P < 0.001) than were cefazolin, vancomycin, or linezolid based on the dose-response profiles. Skin lesion volumes in MSSA-infected animals treated with ceftobiprole were 19 to 29% lower than those for cefazolin-, vancomycin-, or linezolid-treated animals (P < 0.001). In MRSA infections, lesion size in ceftobiprole-treated mice was 34% less than that with cefazolin or linezolid treatment (P < 0.001). Against P. aeruginosa, ceftobiprole at similar doses was as effective as meropenem-cilastatin in reductions of CFU/g skin, despite 8- and 32-fold-lower MICs for meropenem; both treatments were more effective than was cefepime (P < 0.001) against the inducible and overproducing AmpC beta-lactamase strains of P. aeruginosa. Ceftobiprole was similar to meropenem-cilastatin and 47 to 54% more effective than cefepime (P < 0.01) in reducing the size of the lesion caused by either strain of P. aeruginosa in this study. These studies indicate that ceftobiprole is effective in reducing both bacterial load and lesion volume associated with infections due to MSSA, MRSA, and P. aeruginosa in this murine model of skin and soft tissue infection.
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Pharmacodynamic profiling of ceftobiprole for treatment of complicated skin and skin structure infections. Antimicrob Agents Chemother 2009; 53:3371-4. [PMID: 19528285 DOI: 10.1128/aac.01653-08] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Ceftobiprole, a broad-spectrum cephalosporin with activity against methicillin (meticillin)-resistant staphylococci, was statistically noninferior to a combination of vancomycin plus ceftazidime in patients with complicated skin and skin structure infections (cSSSI). This analysis used data from this clinical trial to determine the relationship between therapeutic outcome and the percentage of time that the unbound ceftobiprole concentration exceeds the MIC (percent T>MIC). From the trial of ceftobiprole (500 mg every 8 h, 2-h infusion) for cSSSI due to gram-positive and/or gram-negative bacteria, data from 309 patients in the microbiological intent-to-treat analysis set with measured ceftobiprole concentrations and baseline MICs were used to assess the relationship between percent T>MIC and therapeutic outcome. Individual pharmacokinetic (PK) profiles were obtained from a three-compartment population PK model. The relationship between percent T>MIC and a clinical cure was determined. For the clinical trial dosing regimen, individual percent T>MICs were used to calculate fractional target attainment rates (TARs) for >or=30 and >or=50% T>MIC targets at various MICs. There was a statistically significant relationship between achieving a >or=30 or >or=50% T>MIC and a clinical cure (P = 0.003 and P = 0.007, respectively; Pearson's chi(2) test). The fractional TAR was greater than 90% at a MIC of <or=4 mg/liter for patients with normal renal function. A relationship between percent T>MIC and a clinical cure with ceftobiprole was demonstrated. A ceftobiprole regimen of 500 mg every 8 h as a 2-h infusion has a high probability of achieving a target of >or=30 or >or=50% T>MIC for patients with cSSSI due to gram-positive and gram-negative pathogens.
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Abstract
The increasing threat of antimicrobial resistance in general, and that of methicillin-resistant Staphylococcus aureus (MRSA) in particular, is raising significant medical, economical and public health challenges worldwide, both within hospitals and throughout the community. These considerations, along with the extensive time and costs associated with the development and approval of new therapeutic agents, represent some of the major reasons why understanding the advantages and limitations of new antibiotics, ensuring their judicious use and maximising their active shelf life should become global priorities. On March 18, 2008, the Food and Drug Administration issued an approvable letter for ceftobiprole, a broad-spectrum beta-lactam antibiotic active against MRSA and other clinically relevant Gram-positive and Gram-negative pathogens. Ceftobiprole is currently available only for parenteral administration, and besides its remarkable antimicrobial spectrum, this antibiotic possesses additional desirable characteristics, such as low propensity to select for resistance, efficacy in animal models of disease and good safety profile. Furthermore, in recently completed clinical trials, ceftobiprole demonstrated non-inferiority to comparator compounds such as vancomycin, and emerged as a promising clinical option of monotherapy for the treatment of complicated skin and skin structure infections and community-acquired pneumonia. Here, we discuss some of the most important clinically relevant findings on ceftobiprole obtained from in vitro studies, animal models of disease and recently completed phase III clinical trials.
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Affiliation(s)
- R A Stein
- Department of Pathology, New York University School of Medicine, New York, NY, USA.
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Vidaillac C, Rybak MJ. Ceftobiprole: First Cephalosporin with Activity Against Methicillin-ResistantStaphylococcus aureus. Pharmacotherapy 2009; 29:511-25. [DOI: 10.1592/phco.29.5.511] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Gudiol F, Aguado JM, Pascual A, Pujol M, Almirante B, Miró JM, Cercenado E, Domínguez MDLA, Soriano A, Rodríguez-Baño J, Vallés J, Palomar M, Tornos P, Bouza E. [Consensus document for the treatment of bacteremia and endocarditis caused by methicillin-resistent Staphylococcus aureus. Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica]. Enferm Infecc Microbiol Clin 2009; 27:105-15. [PMID: 19254641 DOI: 10.1016/j.eimc.2008.09.003] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2008] [Accepted: 12/10/2008] [Indexed: 12/15/2022]
Abstract
Bacteremia and endocarditis due to methicillin-resistant Staphylococcus aureus (MRSA) are prevalent and clinically important. The rise in MRSA bacteremia and endocarditis is related with the increasing use of venous catheters and other vascular procedures. Glycopeptides have been the reference drugs for treating these infections. Unfortunately their activity is not completely satisfactory, particularly against MRSA strains with MICs > 1 microg/mL. The development of new antibiotics, such as linezolid and daptomycin, and the promise of future compounds (dalvabancin, ceftobiprole and telavancin) may change the expectatives in this field.The principal aim of this consensus document was to formulate several recommendations to improve the outcome of MRSA bacteremia and endocarditis, based on the latest reported scientific evidence. This document specifically analyzes the approach for three clinical situations: venous catheter-related bacteremia, persistent bacteremia, and infective endocarditis due to MRSA.
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Affiliation(s)
- Francisco Gudiol
- Servicio de Enfermedades Infecciosas, IDIBELL, Hospital Universitario de Bellvitge, Barcelona, España
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Livermore DM. Future directions with daptomycin. J Antimicrob Chemother 2008; 62 Suppl 3:iii41-iii49. [DOI: 10.1093/jac/dkn371] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
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In vivo pharmacodynamics of ceftobiprole against multiple bacterial pathogens in murine thigh and lung infection models. Antimicrob Agents Chemother 2008; 52:3492-6. [PMID: 18676887 DOI: 10.1128/aac.01273-07] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Ceftobiprole medocaril is the parenteral prodrug of ceftobiprole, a novel pyrrolidinone broad-spectrum cephalosporin with in vitro and in vivo bactericidal activities against methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae (PRSP). We have used murine thigh and lung infection models in neutropenic and normal mice to characterize the in vivo pharmacokinetic (PK)-pharmacodynamic (PD) activities of ceftobiprole against multiple strains of S. aureus (including MRSA), S. pneumoniae (including PRSP), and gram-negative bacilli. Serum levels of ceftobiprole following the administration of multiple doses were determined by a microbiological assay. In vivo bactericidal activities and postantibiotic effects (PAEs) of ceftobiprole against MRSA and PRSP strains were determined from serial CFU/thigh values following single doses of ceftobiprole (40 and 160 mg/kg of body weight). Dose fractionation studies were used to determine which PK-PD index correlated best with activity. Magnitudes of the PK-PD indices were calculated from MICs and PK parameters. A sigmoid dose-response model was used to estimate the dose (mg/kg/24 h) required to achieve a static and 2-log(10) kill effects over 24 h. PK results showed area under the concentration-time curve/dose values of 1.8 to 2.8 and half-lives of 0.29 to 0.51 h. MICs ranged from 0.015 to 2 microg/ml. Ceftobiprole demonstrated time-dependent killing; its in vivo PAEs varied from 3.8 h to 4.8 h for MRSA and from 0 to 0.8 h for PRSP. The time above MIC (T > MIC) correlated best with efficacy for both MRSA and PRSP. The T > MIC values required for the static doses were significantly longer (P < 0.001) for Enterobacteriaceae (36 to 45%) than for S. aureus (14 to 28%) and S. pneumoniae (15 to 22%). The drug showed activities in the lung model similar to those in the thigh model. The presence of neutrophils significantly enhanced the activity of ceftobiprole against S. pneumoniae but only slightly against Klebsiella pneumoniae. Based on its PD profile, ceftobiprole is a promising new beta-lactam agent with activity against gram-negative and gram-positive organisms including MRSA and PRSP.
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Comparative study of the susceptibilities of major epidemic clones of methicillin-resistant Staphylococcus aureus to oxacillin and to the new broad-spectrum cephalosporin ceftobiprole. Antimicrob Agents Chemother 2008; 52:2709-17. [PMID: 18505853 DOI: 10.1128/aac.00266-08] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Multidrug-resistant strains of Staphylococcus aureus continue to increase in frequency worldwide, both in hospitals and in the community, raising serious problems for the chemotherapy of staphylococcal disease. Ceftobiprole (BPR; BAL9141), the active constituent of the prodrug ceftobiprole medocaril (BAL5788), is a new cephalosporin which was already shown to have powerful activity against a number of bacterial pathogens, including S. aureus. In an effort to test possible limits to the antibacterial spectrum and efficacy of BPR, we examined the susceptibilities of the relatively few pandemic methicillin-resistant S. aureus (MRSA) clones that are responsible for the great majority of cases of staphylococcal disease worldwide. We also included in the tests the highly oxacillin-resistant subpopulations that are present with low frequencies in the cultures of these clones. Such subpopulations may represent a natural reservoir from which MRSA strains with decreased susceptibility to BPR may emerge in the future. We also tested the efficacy of BPR against MRSA strains with reduced susceptibility to vancomycin and against MRSA strains carrying the enterococcal vancomycin resistance gene complex. BPR was shown to be uniformly effective against all these resistant MRSA strains, and the mechanism of superb antimicrobial activity correlated with the strikingly increased affinity of the cephalosporin against penicillin-binding protein 2A, the protein product of the antibiotic resistance determinant mecA.
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Ceftobiprole: breaking therapeutic dogmas of the β-lactam class. Diagn Microbiol Infect Dis 2008; 61:82-5. [DOI: 10.1016/j.diagmicrobio.2008.02.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2008] [Accepted: 02/25/2008] [Indexed: 11/20/2022]
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Pharmacokinetic and pharmacodynamic profile of ceftobiprole. Diagn Microbiol Infect Dis 2008; 61:96-102. [DOI: 10.1016/j.diagmicrobio.2008.02.013] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2008] [Accepted: 02/25/2008] [Indexed: 11/20/2022]
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Makinson A, Le Moing V. [New anti-Gram+antibiotics: which role in infective endocarditis?]. Ann Cardiol Angeiol (Paris) 2008; 57:88-92. [PMID: 18395180 DOI: 10.1016/j.ancard.2008.02.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2008] [Accepted: 02/21/2008] [Indexed: 05/26/2023]
Abstract
Though the increased resistance to antibiotics observed worldwide is not a major concern in France, treatment of methicillin-resistant S. aureus has important limitations. New antibiotics have recently been marketed or will soon be (quinupristin-dalfopristin, linelozide, tigecyclin, daptomycin, ceftobiprole, dalbavancin). Their role, which has been documented in several forms of acute infections, remains to be established in infective endocarditis. At present, only treatment of methicillin-resistant S. aureus right-sided endocarditis justifies the use of daptomycin, preferably in association with rifampicin, when the use of vancomycin is not possible or contraindicated.
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Affiliation(s)
- A Makinson
- Maladies infectieuses et tropicales, hôpital Gui-de-Chauliac, CHRU de Montpellier, 80, avenue Augustin-Fliche, 34295 Montpellier cedex 5, France
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Noel GJ, Bush K, Bagchi P, Ianus J, Strauss RS. A Randomized, Double-Blind Trial Comparing Ceftobiprole Medocaril with Vancomycin plus Ceftazidime for the Treatment of Patients with Complicated Skin and Skin-Structure Infections. Clin Infect Dis 2008; 46:647-55. [DOI: 10.1086/526527] [Citation(s) in RCA: 196] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
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Widmer AF. Ceftobiprole: A New Option for Treatment of Skin and Soft-Tissue Infections due to Methicillin-Resistant Staphylococcus aureus. Clin Infect Dis 2008; 46:656-8. [DOI: 10.1086/526528] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
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Jones ME. In-vitro profile of a new beta-lactam, ceftobiprole, with activity against methicillin-resistant Staphylococcus aureus. Clin Microbiol Infect 2007; 13 Suppl 2:17-24. [PMID: 17488372 DOI: 10.1111/j.1469-0691.2007.01722.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Ceftobiprole is a novel, broad-spectrum cephalosporin with in-vitro activity against common Gram-positive and Gram-negative organisms. It forms a stable inhibitory complex with Staphylococcus aureus penicillin-binding protein (PBP) 2' (2a), resulting in enhanced activity against methicillin-resistant S. aureus (MRSA). In recent studies of methicillin-susceptible S. aureus, the ceftobiprole MIC(90) value was most frequently < or =1.0 mg/L (MIC range < or =0.25-1.0 mg/L). For MRSA, MIC(90) values were generally 2.0 mg/L (MIC range < or =0.06-4.0 mg/L). MICs for all streptococcal species, except penicillin-resistant Streptococcus viridans but including penicillin-resistant Streptococcus pneumoniae, ranged from < or =0.008 to 2.0 mg/L. Ceftobiprole is active against Enterococcus faecalis (MIC(90) = 4 mg/L), but not generally active against Enterococcus faecium (MIC(90) > 16 mg/L). Ceftobiprole displayed bactericidal activity against Gram-negative pathogens comparable to that of cefepime, ceftazidime or piperacillin-tazobactam in early studies. However, recent data show activity against Pseudomonas aeruginosa similar to that of cefepime but less than that of ceftazidime. Ceftobiprole, like cefepime, is stable in the presence of most class A non-extended spectrum beta-lactamases and inducible class C beta-lactamases. Ceftobiprole is a poor inducer of AmpC beta-lactamase and a poor substrate for hydrolysis by AmpC beta-lactamase. Studies of ceftobiprole in several animal models have demonstrated potent in-vivo efficacy against infections caused by MRSA, including strains intermediately resistant to vancomycin. It was also efficacious in murine infections caused by Gram-negative bacteria with MIC values < or =2 mg/L. The broad spectrum of activity demonstrated by ceftobiprole in vitro and in vivo suggests that it may have potential for empirical treatment of suspected Gram-negative and Gram-positive infections, including those caused by MRSA.
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Affiliation(s)
- M E Jones
- Eurofins Medinet (Anti-Infective Services) Inc., 13665 Dulles Technology Drive, Herndon, VA 20171, USA.
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Results of a double-blind, randomized trial of ceftobiprole treatment of complicated skin and skin structure infections caused by gram-positive bacteria. Antimicrob Agents Chemother 2007; 52:37-44. [PMID: 17954698 DOI: 10.1128/aac.00551-07] [Citation(s) in RCA: 144] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Ceftobiprole is the first broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA) to be assessed in late-stage clinical trials. As a pivotal step in the clinical development of ceftobiprole, a multicenter, global, randomized, double-blind trial was conducted to compare the efficacy of ceftobiprole to that of vancomycin in patients with complicated skin and skin structure infections (cSSSIs) caused by gram-positive bacteria. The primary objective was to assess noninferiority on the basis of the cure rates 7 to 14 days after the completion of therapy in patients administered ceftobiprole 500 mg every 12 h or vancomycin 1 g every 12 h. Of 784 patients randomized, 282 receiving ceftobiprole and 277 receiving vancomycin were clinically evaluable. Of these patients, 93.3% treated with ceftobiprole and 93.5% treated with vancomycin were cured (95% confidence interval of difference, -4.4%, 3.9%). The cure rates for patients with MRSA infections were 91.8% (56/61) with ceftobiprole treatment and 90.0% (54/60) with vancomycin treatment (95% confidence interval of difference, -8.4%, 12.1%). At least one adverse event (AE) was reported by 52% of the ceftobiprole-treated patients and 51% of the vancomycin-treated patients. The most common AEs reported by the ceftobiprole-treated patients were nausea (14%) and taste disturbance (8%). Discontinuation of the study drug because of treatment-emergent AEs occurred in 4% (n = 17) of the ceftobiprole-treated patients and 6% (n = 22) of the vancomycin-treated patients. The results of this trial support the use of ceftobiprole as an effective and well-tolerated treatment option for patients with cSSSIs caused by a spectrum of gram-positive bacteria.
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Tacconelli E, Cataldo MA. Antimicrobial therapy ofStaphylococcus aureusbloodstream infection. Expert Opin Pharmacother 2007; 8:2505-18. [DOI: 10.1517/14656566.8.15.2505] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Bal AM, Gould IM. Antibiotic resistance in Staphylococcus aureus and its relevance in therapy. Expert Opin Pharmacother 2007; 6:2257-69. [PMID: 16218886 DOI: 10.1517/14656566.6.13.2257] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Staphylococcus aureus is a major cause of infections. Only approximately 20% of the strains remain sensitive to penicillin. Beta-lactamase stable penicillins such as flucloxacillin form the mainstay of treatment of staphylococcal infection. Meticillin-resistant S. aureus (MRSA) are resistant to all beta-lactam antibiotics. Glycopeptide antibiotics are effective against most MRSA strains but, in the last few years, isolates of MRSA that have reduced susceptibility to glycopeptides (glycopeptide-intermediate S. aureus) have been isolated. Some strains exhibit frank resistance to glycopeptides (vancomycin-resistant S. aureus). Infections due to these strains are difficult to treat. This review summarises the therapeutic options for MRSA, glycopeptide-intermediate S. aureus and vancomycin-resistant S. aureus. Novel therapeutic strategies such as immunotherapy and vaccines are also discussed.
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Affiliation(s)
- Abhijit M Bal
- Department of Medical Microbiology, Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB25 2ZN, Scotland.
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Arias CA, Singh KV, Panesso D, Murray BE. Evaluation of ceftobiprole medocaril against Enterococcus faecalis in a mouse peritonitis model. J Antimicrob Chemother 2007; 60:594-8. [PMID: 17606481 DOI: 10.1093/jac/dkm237] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
OBJECTIVES Ceftobiprole is a novel broad-spectrum cephalosporin with good in vitro activity against methicillin-resistant Staphylococcus aureus and Enterococcus faecalis. The objective of this study was to assess the in vivo activity of ceftobiprole against four strains of E. faecalis, including beta-lactamase- producing (Bla+) and vancomycin-resistant strains. METHODS Mice were infected intraperitoneally with strains of E. faecalis: (i) the Bla+ strain HH22; (ii) two vancomycin-resistant strains (TX2484 and V583); and (iii) OG1RF (a laboratory strain), using 10 x the LD50 for each strain. Ceftobiprole doses of 25, 12.5 and 6.25 mg/kg (single doses) and ampicillin 50, 25, 12.5 and 6.25 mg/kg (single and double doses) were administered subcutaneously immediately after bacterial challenge and mice were monitored for 96 h. RESULTS All four E. faecalis had ceftobiprole MICs <or=0.5 mg/L. Despite being susceptible in vitro at the standard inoculum, ampicillin (single and double doses) did not protect mice against intraperitoneal challenge with Bla+ E. faecalis HH22, with a 50% protective dose (PD50) of >100 mg/kg, whereas ceftobiprole was protective (PD50 of 2 mg/kg). Ceftobiprole PD50s for vancomycin-resistant isolates TX2484 and V583 were 7.7 and 5.2 mg/kg, respectively, similar to those of single dose ampicillin (12.5 and 16.4 mg/kg, respectively). For OG1RF, both ampicillin and ceftobiprole protected all mice at doses of 25 and 12.5 mg/kg, respectively, with a PD50 of 4.2 and 8 mg/kg for ceftobiprole and ampicillin, respectively. CONCLUSIONS Ceftobiprole had comparable in vivo activity to that of ampicillin against vancomycin-resistant and ampicillin-susceptible strains of E. faecalis in the mouse peritonitis model. Ceftobiprole was superior in vivo to ampicillin against the Bla+ strain HH22. Our data support the further study of ceftobiprole as a therapeutic agent in humans infected with E. faecalis.
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Affiliation(s)
- Cesar A Arias
- Center for the Study of Emerging and Reemerging Pathogens, Division of Infectious Diseases, University of Texas Medical School at Houston, 6431 Fannin Street, MSB 2.112, Houston, TX 77030, USA
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Davies TA, Page MGP, Shang W, Andrew T, Kania M, Bush K. Binding of ceftobiprole and comparators to the penicillin-binding proteins of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae. Antimicrob Agents Chemother 2007; 51:2621-4. [PMID: 17470659 PMCID: PMC1913263 DOI: 10.1128/aac.00029-07] [Citation(s) in RCA: 131] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Ceftobiprole exhibited tight binding to PBP2a in methicillin-resistant Staphylococcus aureus, PBP2x in penicillin-resistant Streptococcus pneumoniae, and PBP3 and other essential penicillin-binding proteins in methicillin-susceptible S. aureus, Escherichia coli, and Pseudomonas aeruginosa. Ceftobiprole also bound well to PBP2 in the latter organisms, contributing to the broad-spectrum antibacterial activity against gram-negative and gram-positive bacteria.
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Affiliation(s)
- Todd A Davies
- Johnson & Johnson Pharmaceutical Research and Development, LLC, Room B225, 1000 Route 202, Raritan, NJ 08869, USA.
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