LB11058, a New Cephalosporin with High Penicillin-Binding Protein 2a Affinity and Activity in Experimental Endocarditis Due to Homogeneously Methicillin-Resistant
            <i>Staphylococcus aureus</i>

Vouillamoz, Jacques; Entenza, José M.; Hohl, P.; Moreillon, Philippe

doi:10.1128/aac.48.11.4322-4327.2004

Cited by 18 publications

(6 citation statements)

References 31 publications

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“…The new synthetic cephalosporin LB11058 has good affinity for staphylococcal penicillinbinding protein 2a (PBP2a). At appropriate doses, LB11058 was effective both in vitro and in vivo in a rat aortic MRSA endocarditis model [75]. This finding supports the development of this agent for the treatment of MRSA infections.…”

Section: Future Studiessupporting

confidence: 64%

Emerging Issues in the Diagnosis and Management of Infections Caused by Multi-Drug-Resistant, Gram-Positive Cocci

Napolitano¹

2005

Surgical Infections

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Background: Rising rates of multi-drug-resistant, gram-positive cocci (e.g., methicillin-resistant Staphylococcus aureus [MRSA], vancomycin-resistant Enterococcus spp. [VRE]) have created treatment challenges for clinicians in both the hospital and community settings. These organisms have become especially problematic for hospitalized patients with pneumonia, complicated intra-abdominal infections, and skin and skin-structure infections (SSSIs).Methods: A review of the recent literature (1990 onwards) was undertaken in order to review the epidemiology, diagnostic issues, and clinical trial data of available and forthcoming therapies for the treatment of multi-drug resistant, gram-positive isolates, with an emphasis on selected MRSA infections (i.e., pneumonia, SSSI, diabetic foot infections, blood stream) and infections caused by VRE.Results: The rate of healthcare-associated MRSA in 2004 rose to an incidence of 59.5% in the United States compared with data from 1998-2002, making MRSA the predominant grampositive etiology of S. aureus infections in hospitalized patients. Methicillin-resistant S. aureus has also emerged as an important pathogen in both the non-ICU and community settings. Similarly, 28.5% of all enterococcal isolates were identified as vancomycin-resistant in 2003 (a 12% increase). However, these rates may be underestimated, as detection methods for determining susceptibility have proved to be inadequate. Recognition that prior inadequate antibiotic therapy is common in patients with antibiotic-resistant bacteria, and is associated with higher mortality rates, emphasizes the importance of selecting appropriate empiric therapy. Currently available therapies for resistant gram-positive infections include quinupristindalfopristin, linezolid, and daptomycin, although each of these agents has limitations (e.g., daptomycin is not indicated for MRSA pneumonia due to inadequate lung tissue penetration and inactivation by surfactant). Three agents with broad-spectrum activity against gram-positive organisms that are at an advanced stage of testing include two new glycopeptides (oritavancin and dalbavancin), and a first-in-class glycylcycline (tigecycline). These agents have demonstrated efficacy in the treatment of SSSIs, including those caused by MRSA.Conclusions: New antimicrobial agents are needed to combat the increasing prevalence of multi-drug-resistant, gram-positive pathogens such as MRSA. The emergence of resistance to available therapies such as vancomycin underscores this urgency.

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Section: Future Studiessupporting

confidence: 64%

Emerging Issues in the Diagnosis and Management of Infections Caused by Multi-Drug-Resistant, Gram-Positive Cocci

Napolitano¹

2005

Surgical Infections

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“…Staphylococcus aureus is able to accumulate mechanisms of resistance to all clinically available compounds, including In the present circumstances, the search for new agents targeting the cell wall and, more specifically, the PBPs is a promising approach (4,10,16,17). The in vitro study of ceftaroline and comparison of the results with those obtained with the comparators confirmed the excellent activity of this new drug against MRSA strains.…”

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confidence: 79%

In Vivo Efficacy of Ceftaroline (PPI-0903), a New Broad-Spectrum Cephalosporin, Compared with Linezolid and Vancomycin against Methicillin-Resistant and Vancomycin-Intermediate Staphylococcus aureus in a Rabbit Endocarditis Model

Jacqueline

Caillon

Mabecque

et al. 2007

Antimicrob Agents Chemother

107

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Using the rabbit endocarditis model, we compared the activity of a new broad-spectrum cephalosporin, ceftaroline, with those of linezolid and vancomycin against methicillin-resistant Staphylococcus aureus. After a 4-day treatment, ceftaroline exhibited superior bactericidal in vivo activity against resistant S. aureus strains and appeared to be the most effective drug against a heterogeneous glycopeptide-intermediate S. aureus strain.Ceftaroline is a novel broad-spectrum cephalosporin with potent activity against methicillin-resistant Staphylococcus aureus (MRSA) strains due to its strong affinity for S. aureus penicillin-binding proteins (PBPs), including PBP 2A, the additional protein responsible for the methicillin resistance mechanism (6, 15). Ceftaroline acetate (PPI-0903) is an Nphosphono water-soluble prodrug rapidly metabolized in vivo into the bioactive metabolite ceftaroline . No study has been performed by using a challenging rabbit infection model of experimental endocarditis, which has proved to be highly valuable in evaluating the in vivo effectiveness of antibiotics. The aim of the present study was to evaluate the in vivo activity of ceftaroline compared with those of other antistaphylococcal drugs by using a rabbit model of aortic valve endocarditis with doses projected to be therapeutic for humans.We studied two MRSA strains isolated from blood cultures. The MRSA strain (originally designated SA-2) was a strain with heterogeneous high-level methicillin resistance (methicillin MIC ϭ 128 mg/liter) (7), and the heterogeneous glycopeptide-intermediate S. aureus strain (hGISA) exhibited homogeneous resistance to methicillin (methicillin MIC Ͼ 1,024 mg/ liter) and heterogeneous resistance to glycopeptides (8). The MICs were determined in cation-supplemented Mueller-Hinton broth by the microdilution technique (1, 11). Bactericidal activity was assessed on the basis of the determination of minimal bactericidal concentrations (MBCs) by the microdilution method and on the basis of the results of time-kill experiments with an inoculum of 5 ϫ 10 6 CFU/ml (12). High-performance liquid chromatography was used to determine the concentrations of linezolid (13) (lower detection limit, 0.1 mg/liter; coefficient of variation, Ͻ10%). Assays with vancomycin were performed by an immunoenzymatic method with a COBAS MIRA unit and EMIT reagents (Behring Diagnostics Inc., Cupertino, CA) (detection threshold, 2.5 mg/ liter; coefficient of variation, 4.1 to 6.9%). Active ceftaroline concentrations were determined by a microbiologic assay with Bacillus subtilis as the test organism and antibiotic medium 2 (Difco Laboratories, Detroit, MI) as the diffusion medium (lower detection limit, 0.25 mg/liter; intraday and interday variations, Ͻ10%). Simulation of the pharmacokinetics of linezolid was performed as validated previously (7). For ceftaroline, blood samples were taken from six healthy rabbits after administration of a ceftaroline acetate bolus of 10 and 30 mg/kg of body weight in order to determine the spontaneous drug ...

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“…Hence, suppression of PBP2a production is a promising approach to overcome MRSA's resistance. By doing so, there is a possibility to restore the susceptibility of MRSA to beta-lactam antibiotics [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Reversal of Ampicillin Resistance in MRSA via Inhibition of Penicillin-Binding Protein 2a byAcalypha wilkesiana

Santiago

Pang

Lim

et al. 2014

BioMed Research International

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The inhibitory activity of a semipure fraction from the plant, Acalypha wilkesiana assigned as 9EA-FC-B, alone and in combination with ampicillin, was studied against methicillin-resistant Staphylococcus aureus (MRSA). In addition, effects of the combination treatment on PBP2a expression were investigated. Microdilution assay was used to determine the minimal inhibitory concentrations (MIC). Synergistic effects of 9EA-FC-B with ampicillin were determined using the fractional inhibitory concentration (FIC) index and kinetic growth curve assay. Western blot experiments were carried out to study the PBP2a expression in treated MRSA cultures. The results showed a synergistic effect between ampicillin and 9EA-FC-B treatment with the lowest FIC index of 0.19 (synergism ≤ 0.5). The presence of 9EA-FC-B reduced the MIC of ampicillin from 50 to 1.56 μg mL−1. When ampicillin and 9EA-FC-B were combined at subinhibitory level, the kinetic growth curves were suppressed. The antibacterial effect of 9EA-FC-B and ampicillin was shown to be synergistic. The synergism is due the ability of 9EA-FC-B to suppress the activity of PBP2a, thus restoring the susceptibility of MRSA to ampicillin. Corilagin was postulated to be the constituent responsible for the synergistic activity showed by 9EA-FC-B.

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LB11058, a New Cephalosporin with High Penicillin-Binding Protein 2a Affinity and Activity in Experimental Endocarditis Due to Homogeneously Methicillin-Resistant Staphylococcus aureus

Cited by 18 publications

References 31 publications

Emerging Issues in the Diagnosis and Management of Infections Caused by Multi-Drug-Resistant, Gram-Positive Cocci

Emerging Issues in the Diagnosis and Management of Infections Caused by Multi-Drug-Resistant, Gram-Positive Cocci

In Vivo Efficacy of Ceftaroline (PPI-0903), a New Broad-Spectrum Cephalosporin, Compared with Linezolid and Vancomycin against Methicillin-Resistant and Vancomycin-Intermediate Staphylococcus aureus in a Rabbit Endocarditis Model

Reversal of Ampicillin Resistance in MRSA via Inhibition of Penicillin-Binding Protein 2a byAcalypha wilkesiana

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