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Ronald N Jones - One of the best experts on this subject based on the ideXlab platform.
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Evolution of Ceftaroline-Resistant Mrsa in a Child with Cystic Fibrosis Following Repeated Antibiotic Exposure.
Pediatric Infectious Disease Journal, 2016Co-Authors: Christopher R. Cannavino, Ian A Critchley, Donald Biek, Helio S Sader, David J Farrell, Rodrigo E Mendes, Ronald N Jones, Jennifer Le, Shannon M. Skochko, John S. BradleyAbstract:: Ceftaroline is the first β-lactam antibiotic with activity against methicillin-resistant Staphylococcus aureus (MRSA). We describe a Ceftaroline-resistant MRSA strain, isolated from a girl with cystic fibrosis after 22 Ceftaroline treatment courses. MRSA genome sequencing documented a Tyr446Asn alteration in penicillin binding protein 2 that appeared responsible for resistance. Noncompartmental Ceftaroline pharmacokinetic evaluation in our patient documented increased clearance and volume of distribution compared with adults.
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Ceftaroline activity tested against viridans group streptococci from US hospitals
Diagnostic Microbiology and Infectious Disease, 2015Co-Authors: Helio S Sader, Mariana Castanheira, David J Farrell, Rodrigo E Mendes, Robert K Flamm, Paul R. Rhomberg, Ronald N JonesAbstract:A total of 840 clinically relevant viridans group streptococci (VGS) isolates (1/patient episode) were collected from 71 US medical centers in 2013-2014. These organisms were tested for susceptibility by reference broth microdilution methods against Ceftaroline and selected comparator agents. All isolates were speciated by matrix-assisted laser desorption ionization-time-of-flight (MALDI-TOF) mass spectrometry and were primarily from skin/soft tissue (32.6%) and bloodstream (32.3%) infections. Ceftaroline was highly active against all VGS species/groups with MIC50 and MIC90 values ranging from ≤0.015 to 0.03μg/mL and ≤0.015 to 0.06μg/mL, respectively. The highest Ceftaroline MIC value was only 0.5μg/mL (0.5% of strains) and Ceftaroline (MIC50/90, 0.03/0.06μg/mL) was 8-fold more active than ceftriaxone (MIC50/90, 0.25/0.5μg/mL). The VGS groups most susceptible to Ceftaroline were Streptococcus mutans and Streptococcus bovis (MIC90, ≤0.015μg/mL), whereas the highest Ceftaroline MIC values were observed among Streptococcus mitis and Streptococcus sanguinis groups. In summary, Ceftaroline exhibited potent in vitro activity against VGS, including many uncommonly isolated species/groups for which very limited susceptibility information is currently available to guide therapy.
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Ceftaroline activity against bacterial pathogens frequently isolated in u s medical centers results from five years of the aware surveillance program
Antimicrobial Agents and Chemotherapy, 2015Co-Authors: Helio S Sader, David J Farrell, Robert K Flamm, Jennifer M Streit, Ronald N JonesAbstract:ABSTRACT A total of 84,704 isolates were collected from 191 medical centers in 2009 to 2013 and tested for susceptibility to Ceftaroline and comparator agents by broth microdilution methods. Ceftaroline inhibited all Staphylococcus aureus isolates at ≤2 μg/ml and was very active against methicillin-resistant strains (MIC at which 90% of the isolates tested are inhibited [MIC 90 ], 1 μg/ml; 97.6% susceptible). Among Streptococcus pneumoniae isolates, the highest Ceftaroline MIC was 0.5 μg/ml, and Ceftaroline activity against the most common Enterobacteriaceae species (MIC 50 , 0.12 μg/ml; 78.9% susceptible) was similar to that of ceftriaxone (MIC 50 , ≤0.25 μg/ml; 86.8% susceptible).
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Ceftaroline clinical and microbiology experience with focus on methicillin resistant staphylococcus aureus after regulatory approval in the usa
Diagnostic Microbiology and Infectious Disease, 2015Co-Authors: Martin E Stryjewski, Ronald N Jones, Ralph G CoreyAbstract:Abstract Ceftaroline fosamil was approved in 2010 by the United States Food and Drug Administration (USA-FDA) for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSIs) and community-acquired bacterial pneumonia (CABP). After approval, several studies and case reports have described the postmarketing clinical experience with Ceftaroline in ABSSSIs and CABP and in patients with invasive methicillin-resistant Staphylococcus aureus (MRSA) infections, many of whom had failed prior antibiotics. Successful clinical outcomes observed among the majority of these patients were supported by preapproval and postapproval in vitro surveillance of Ceftaroline activity using breakpoint criteria that have been harmonized between the USA-FDA and CLSI. MIC 90 values/percentage of strains susceptible to Ceftaroline has remained stable over the period 2009–2012. Taken together, these postapproval studies support the use of Ceftaroline for ABSSSI as well as CABP. Importantly, these data also suggest that Ceftaroline can be effective in patients with serious invasive MRSA infections who have failed other therapies.
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Ceftaroline activity against bacterial organisms isolated from acute bacterial skin and skin structure infections in united states medical centers 2009 2011
Diagnostic Microbiology and Infectious Disease, 2014Co-Authors: Michael A Pfaller, Helio S Sader, Robert K Flamm, Ronald N JonesAbstract:Ceftaroline, the active metabolite of the prodrug Ceftaroline fosamil, is a new cephalosporin with bactericidal activity against resistant Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant strains of Streptococcus pneumoniae, and commonly isolated Gram-negative organisms, including ceftriaxone-susceptible Enterobacteriaceae. We evaluated the in vitro activity of Ceftaroline and selected comparator agents against bacterial isolates collected from patients with acute bacterial skin and skin structure infections (ABSSSIs) in the USA. A total of 6222 isolates were collected from 67 medical centers distributed across all nine USA census regions between 2009 and 2011 and tested for susceptibility by reference broth microdilution methods. Ceftaroline was very active against S. aureus (MIC50/90, 0.5/1 μg/mL; 99.6% susceptible), including MRSA (MIC50/90, 0.5/1 μg/mL; 99.1% susceptible). Against β-hemolytic streptococci, the activity of Ceftaroline (MIC50/90, ≤0.015/0.03 μg/mL; 100.0% susceptible) was comparable to that of both penicillin (MIC50/90, ≤0.06/≤0.06 μg/mL; 100.0% susceptible) and ceftriaxone (MIC50/90, ≤0.25/≤0.25 μg/mL; 100.0% susceptible). Ceftaroline was also highly active against viridans group streptococci (MIC50/90, 0.03/0.06 μg/mL). Similar to ceftriaxone and ceftazidime, Ceftaroline was active against wild-type strains of Escherichia coli (MIC50/90, 0.12/0.25 μg/mL; 94.0% susceptible) and Klebsiella pneumoniae (MIC50/90, 0.12/0.25 μg/mL; 96.8% susceptible); however, the Ceftaroline activity was compromised among strains with an extended-spectrum β-lactamase-phenotype (MIC50/90, >32/>32 μg/mL for both E. coli and K. pneumoniae). In summary, Ceftaroline showed potent activity against a large contemporary collection (6222) of bacterial isolates associated with ABSSSI in the USA.
Michael J Rybak - One of the best experts on this subject based on the ideXlab platform.
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examining the use of Ceftaroline in the treatment of streptococcus pneumoniae meningitis with reference to human cathelicidin ll 37
Antimicrobial Agents and Chemotherapy, 2015Co-Authors: George Sakoulas, Michael J Rybak, Poochit Nonejuie, Ravina Kullar, Joe Pogliano, Victor NizetAbstract:Five cases of bacterial meningitis treated with Ceftaroline (4 Streptococcus pneumoniae and 1 Staphylococcus aureus) are summarized here. The pharmacodynamics of human cathelicidin LL-37 and Ceftaroline were evaluated against S. pneumoniae. Patients who received Ceftaroline 600 mg every 8 h (q8h) (1 S. aureus and 3 S. pneumoniae) were successfully treated; treatment failed in 1 patient with S. pneumoniae who received 600 mg q12h. Ceftaroline increased the negative surface charge and sensitized S. pneumoniae to killing by LL-37, a peptide implicated in blood-brain barrier defense.
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antimicrobial salvage therapy for persistent staphylococcal bacteremia using daptomycin plus Ceftaroline
Clinical Therapeutics, 2014Co-Authors: George Sakoulas, Michael J Rybak, Pamela A Moise, Anthony M Casapao, Poochit Nonejuie, Joshua Olson, Cheryl Y M Okumura, Ravina Kullar, Abhay Dhand, Warren E RoseAbstract:Abstract Purpose Guidelines recommend daptomycin combination therapy as an option for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia after vancomycin failure. Recent data suggest that combining daptomycin with a β-lactam may have unique benefits; however, there are very limited clinical data regarding the use of Ceftaroline with daptomycin. Methods All 26 cases from the 10 medical centers in which Ceftaroline plus daptomycin was used for treatment of documented refractory staphylococcal bacteremia from March 2011 to November 2012 were included. In vitro (synergy studies, binding assays, cathelicidin LL-37 killing assays), and in vivo (virulence assays using a murine subcutaneous infection model) studies examining the effects of Ceftaroline with daptomycin were also performed. Findings Daptomycin plus Ceftaroline was used in 26 cases of staphylococcal bacteremia (20 MRSA, 2 vancomycin-intermediate S aureus , 2 methicillin-susceptible S aureus [MSSA], 2 methicillin-resistant S epidermidis ). Bacteremia persisted for a median of 10 days (range, 3–23 days) on previous antimicrobial therapy. After daptomycin plus Ceftaroline was started, the median time to bacteremia clearance was 2 days (range, 1–6 days). In vitro studies showed Ceftaroline synergy against MRSA and enhanced MRSA killing by cathelicidin LL-37 and neutrophils. Ceftaroline also induced daptomycin binding in MSSA and MRSA to a comparable degree as nafcillin. MRSA grown in subinhibitory concentrations of Ceftaroline showed attenuated virulence in a murine subcutaneous infection model. Implications Ceftaroline plus daptomycin may be an option to hasten clearance of refractory staphylococcal bacteremia. Ceftaroline offers dual benefit via synergy with both daptomycin and sensitization to innate host defense peptide cathelicidin LL37, which could attenuate virulence of the pathogen.
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evaluation of Ceftaroline vancomycin daptomycin or Ceftaroline plus daptomycin against daptomycin nonsusceptible methicillin resistant staphylococcus aureus in an in vitro pharmacokinetic pharmacodynamic model of simulated endocardial vegetations
Antimicrobial Agents and Chemotherapy, 2014Co-Authors: Brian J Werth, Katie E. Barber, Cortney E Ireland, Michael J RybakAbstract:ABSTRACT Infective endocarditis (IE) caused by methicillin-resistant Staphylococcus aureus (MRSA) with reduced susceptibility to vancomycin and daptomycin has few adequate therapeutic options. Ceftaroline (CPT) is bactericidal against daptomycin (DAP)-nonsusceptible (DNS) and vancomycin-intermediate MRSA, but supporting data are limited for IE. This study evaluated the activities of Ceftaroline, vancomycin, daptomycin, and the combination of Ceftaroline plus daptomycin against DNS MRSA in a pharmacokinetic/pharmacodynamic (PK/PD) model of simulated endocardial vegetations (SEVs). Simulations of Ceftaroline-fosamil (600 mg) every 8 h (q8h) (maximum concentration of drug in serum [ C max ], 21.3 mg/liter; half-life [ t 1/2 ], 2.66 h), daptomycin (10 mg/kg of body weight/day) ( C max , 129.7 mg/liter; t 1/2 , 8 h), vancomycin (1 g) q8h (minimum concentration of drug in serum [ C min ], 20 mg/liter; t 1/2 , 5 h), and Ceftaroline plus daptomycin were evaluated against 3 clinical DNS, vancomycin-intermediate MRSA in a two-compartment, in vitro , PK/PD SEV model over 96 h with a starting inoculum of ∼8 log 10 CFU/g. Bactericidal activity was defined as a ≥3-log 10 CFU/g reduction from the starting inoculum. Therapeutic enhancement of combinations was defined as ≥2-log 10 CFU/g reduction over the most active agent alone. MIC values for daptomycin, vancomycin, and Ceftaroline were 4 mg/liter, 4 to 8 mg/liter, and 0.5 to 1 mg/liter, respectively, for all strains. At simulated exposures, vancomycin was bacteriostatic, but daptomycin and Ceftaroline were bactericidal. By 96 h, Ceftaroline monotherapy offered significantly improved killing compared to other agents against one strain. The combination of DAP plus CPT demonstrated therapeutic enhancement, resulting in significantly improved killing versus either agent alone against 2/3 (67%) strains. CPT demonstrated bactericidal activity against DNS, vancomycin-intermediate MRSA at high bacterial densities. Ceftaroline plus daptomycin may offer more rapid and sustained activity against some MRSA in the setting of high-inoculum infections like IE and should also be considered.
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Ceftaroline increases membrane binding and enhances the activity of daptomycin against daptomycin nonsusceptible vancomycin intermediate staphylococcus aureus in a pharmacokinetic pharmacodynamic model
Antimicrobial Agents and Chemotherapy, 2013Co-Authors: Brian J Werth, Michael J Rybak, George Sakoulas, Warren E Rose, Joe Pogliano, Ryan TewheyAbstract:New antimicrobial agents and novel combination therapies are needed to treat serious infections caused by methicillin-resistant Staphylococcus aureus (MRSA) with reduced susceptibility to daptomycin and vancomycin. The purpose of this study was to evaluate the combination of Ceftaroline plus daptomycin or vancomycin in an in vitro pharmacokinetic/pharmacodynamic model. Simulations of Ceftaroline-fosamil at 600 mg per kg of body weight every 8 h (q8h) (maximum free-drug concentration in serum [fCmax], 15.2 mg/liter; half-life [t1/2], 2.3 h), daptomycin at 10 mg/kg/day (fCmax, 11.3 mg/liter; t1/2, 8 h), vancomycin at 2 g q12h (fCmax, 30 mg/liter; t1/2, 6 h), Ceftaroline plus daptomycin, and Ceftaroline plus vancomycin were evaluated against a clinical, isogenic MRSA strain pair: D592 (daptomycin susceptible and heterogeneous vancomycin intermediate) and D712 (daptomycin nonsusceptible and vancomycin intermediate) in a one-compartment in vitro pharmacokinetic/pharmacodynamic model over 96 h. Therapeutic enhancement of combinations was defined as ≥2 log10 CFU/ml reduction over the most active single agent. The effect of Ceftaroline on the membrane charge, cell wall thickness, susceptibility to killing by the human cathelicidin LL37, and daptomycin binding were evaluated. Therapeutic enhancement was observed with daptomycin plus Ceftaroline in both strains and vancomycin plus Ceftaroline against D592. Ceftaroline exposure enhanced daptomycin-induced depolarization (81.7% versus 72.3%; P = 0.03) and killing by cathelicidin LL37 (P < 0.01) and reduced cell wall thickness (P < 0.001). Fluorescence-labeled daptomycin was bound over 7-fold more in Ceftaroline-exposed cells. Whole-genome sequencing and mutation analysis of these strains indicated that change in daptomycin susceptibility is related to an fmtC (mprF) mutation. The combination of daptomycin plus Ceftaroline appears to be potent, with rapid and sustained bactericidal activity against both daptomycin-susceptible and -nonsusceptible strains of MRSA.
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in vitro evaluation of Ceftaroline alone and in combination with tobramycin against hospital acquired meticillin resistant staphylococcus aureus ha mrsa isolates
International Journal of Antimicrobial Agents, 2010Co-Authors: Celine Vidaillac, Michael J Rybak, Steve N LeonardAbstract:Abstract The aim of this study was to evaluate the in vitro activity of Ceftaroline and its potential for synergy with tobramycin in comparison with vancomycin against a collection of hospital-acquired meticillin-resistant Staphylococcus aureus (HA-MRSA), including isolates with reduced susceptibility to glycopeptides. Ceftaroline, vancomycin, daptomycin and linezolid susceptibilities were determined for 200 HA-MRSA isolates. Four randomly selected strains [including one vancomycin-intermediate S. aureus (VISA) and one heteroresistant VISA (hVISA)] were evaluated in time–kill experiments with Ceftaroline and vancomycin alone or combined with tobramycin at 0.25 and 0.5 times the minimum inhibitory concentration (MIC). MICs for 50% and 90% of the organisms (MIC 50 and MIC 90 , respectively) were both 1 mg/L for Ceftaroline and were 1 mg/L and 2 mg/L, respectively, for vancomycin. The same Ceftaroline MIC ranges (0.25–2 mg/L) were observed for isolates recovered from respiratory tract samples, blood or skin. In time–kill experiments, no synergy was observed at 0.25× MIC against any tested isolates with either Ceftaroline or vancomycin. In contrast, the combination of Ceftaroline plus tobramycin at 0.5× MIC was synergistic against the two MRSA strains and the hVISA but was indifferent against the VISA isolate. In conclusion, Ceftaroline demonstrated antimicrobial activity independently of the specimen source and exhibited lower MICs than vancomycin. Finally, at sub-MIC levels, Ceftaroline plus tobramycin displayed significantly greater activity than vancomycin plus tobramycin against MRSA ( P
Helio S Sader - One of the best experts on this subject based on the ideXlab platform.
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Evolution of Ceftaroline-Resistant Mrsa in a Child with Cystic Fibrosis Following Repeated Antibiotic Exposure.
Pediatric Infectious Disease Journal, 2016Co-Authors: Christopher R. Cannavino, Ian A Critchley, Donald Biek, Helio S Sader, David J Farrell, Rodrigo E Mendes, Ronald N Jones, Jennifer Le, Shannon M. Skochko, John S. BradleyAbstract:: Ceftaroline is the first β-lactam antibiotic with activity against methicillin-resistant Staphylococcus aureus (MRSA). We describe a Ceftaroline-resistant MRSA strain, isolated from a girl with cystic fibrosis after 22 Ceftaroline treatment courses. MRSA genome sequencing documented a Tyr446Asn alteration in penicillin binding protein 2 that appeared responsible for resistance. Noncompartmental Ceftaroline pharmacokinetic evaluation in our patient documented increased clearance and volume of distribution compared with adults.
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Ceftaroline activity tested against viridans group streptococci from US hospitals
Diagnostic Microbiology and Infectious Disease, 2015Co-Authors: Helio S Sader, Mariana Castanheira, David J Farrell, Rodrigo E Mendes, Robert K Flamm, Paul R. Rhomberg, Ronald N JonesAbstract:A total of 840 clinically relevant viridans group streptococci (VGS) isolates (1/patient episode) were collected from 71 US medical centers in 2013-2014. These organisms were tested for susceptibility by reference broth microdilution methods against Ceftaroline and selected comparator agents. All isolates were speciated by matrix-assisted laser desorption ionization-time-of-flight (MALDI-TOF) mass spectrometry and were primarily from skin/soft tissue (32.6%) and bloodstream (32.3%) infections. Ceftaroline was highly active against all VGS species/groups with MIC50 and MIC90 values ranging from ≤0.015 to 0.03μg/mL and ≤0.015 to 0.06μg/mL, respectively. The highest Ceftaroline MIC value was only 0.5μg/mL (0.5% of strains) and Ceftaroline (MIC50/90, 0.03/0.06μg/mL) was 8-fold more active than ceftriaxone (MIC50/90, 0.25/0.5μg/mL). The VGS groups most susceptible to Ceftaroline were Streptococcus mutans and Streptococcus bovis (MIC90, ≤0.015μg/mL), whereas the highest Ceftaroline MIC values were observed among Streptococcus mitis and Streptococcus sanguinis groups. In summary, Ceftaroline exhibited potent in vitro activity against VGS, including many uncommonly isolated species/groups for which very limited susceptibility information is currently available to guide therapy.
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Ceftaroline activity against bacterial pathogens frequently isolated in u s medical centers results from five years of the aware surveillance program
Antimicrobial Agents and Chemotherapy, 2015Co-Authors: Helio S Sader, David J Farrell, Robert K Flamm, Jennifer M Streit, Ronald N JonesAbstract:ABSTRACT A total of 84,704 isolates were collected from 191 medical centers in 2009 to 2013 and tested for susceptibility to Ceftaroline and comparator agents by broth microdilution methods. Ceftaroline inhibited all Staphylococcus aureus isolates at ≤2 μg/ml and was very active against methicillin-resistant strains (MIC at which 90% of the isolates tested are inhibited [MIC 90 ], 1 μg/ml; 97.6% susceptible). Among Streptococcus pneumoniae isolates, the highest Ceftaroline MIC was 0.5 μg/ml, and Ceftaroline activity against the most common Enterobacteriaceae species (MIC 50 , 0.12 μg/ml; 78.9% susceptible) was similar to that of ceftriaxone (MIC 50 , ≤0.25 μg/ml; 86.8% susceptible).
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analysis of staphylococcus aureus clinical isolates with reduced susceptibility to Ceftaroline an epidemiological and structural perspective
Journal of Antimicrobial Chemotherapy, 2014Co-Authors: Robert E Mclaughlin, Joseph P Iaconis, Helio S Sader, Sushmita D. LahiriAbstract:OBJECTIVES: Ceftaroline, approved in Europe in 2012, has activity against methicillin-resistant Staphylococcus aureus (MRSA), with MIC90 values of 1-2 mg/L depending on geographical location. During a global 2010 surveillance programme, conducted prior to the European launch, 4 S. aureus isolates, out of 8037 tested, possessing Ceftaroline MIC values of >2 mg/L were identified. The objective of this study was to characterize these four isolates to elucidate the mechanism of Ceftaroline resistance. METHODS: MIC determinations were performed using broth microdilution and whole genome sequencing was performed to enable sequence-based analyses. RESULTS: The only changes in proteins known to be required for full expression of methicillin resistance that correlated with the Ceftaroline MIC were in penicillin-binding protein 2a (PBP2a). Isolates with a Ceftaroline MIC of 2 mg/L had a Glu239Lys mutation in the non-penicillin-binding domain whereas the four isolates with Ceftaroline MIC values of 8 mg/L carried an additional Glu447Lys mutation in the penicillin-binding domain. The impact of these mutations was analysed using the known X-ray structure of S. aureus PBP2a and a model for Ceftaroline resistance proposed. Analysis of the core genomes showed that the isolates with reduced susceptibility to Ceftaroline were epidemiologically related. CONCLUSIONS: Mutations in PBP2a can affect the activity of Ceftaroline against MRSA. Although a rare event, based on surveillance studies, it appears a first-step change in the non-penicillin-binding domain together with a second-step in the penicillin-binding domain may result in elevation of the Ceftaroline MIC to >2 mg/L.
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Ceftaroline activity against bacterial organisms isolated from acute bacterial skin and skin structure infections in united states medical centers 2009 2011
Diagnostic Microbiology and Infectious Disease, 2014Co-Authors: Michael A Pfaller, Helio S Sader, Robert K Flamm, Ronald N JonesAbstract:Ceftaroline, the active metabolite of the prodrug Ceftaroline fosamil, is a new cephalosporin with bactericidal activity against resistant Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant strains of Streptococcus pneumoniae, and commonly isolated Gram-negative organisms, including ceftriaxone-susceptible Enterobacteriaceae. We evaluated the in vitro activity of Ceftaroline and selected comparator agents against bacterial isolates collected from patients with acute bacterial skin and skin structure infections (ABSSSIs) in the USA. A total of 6222 isolates were collected from 67 medical centers distributed across all nine USA census regions between 2009 and 2011 and tested for susceptibility by reference broth microdilution methods. Ceftaroline was very active against S. aureus (MIC50/90, 0.5/1 μg/mL; 99.6% susceptible), including MRSA (MIC50/90, 0.5/1 μg/mL; 99.1% susceptible). Against β-hemolytic streptococci, the activity of Ceftaroline (MIC50/90, ≤0.015/0.03 μg/mL; 100.0% susceptible) was comparable to that of both penicillin (MIC50/90, ≤0.06/≤0.06 μg/mL; 100.0% susceptible) and ceftriaxone (MIC50/90, ≤0.25/≤0.25 μg/mL; 100.0% susceptible). Ceftaroline was also highly active against viridans group streptococci (MIC50/90, 0.03/0.06 μg/mL). Similar to ceftriaxone and ceftazidime, Ceftaroline was active against wild-type strains of Escherichia coli (MIC50/90, 0.12/0.25 μg/mL; 94.0% susceptible) and Klebsiella pneumoniae (MIC50/90, 0.12/0.25 μg/mL; 96.8% susceptible); however, the Ceftaroline activity was compromised among strains with an extended-spectrum β-lactamase-phenotype (MIC50/90, >32/>32 μg/mL for both E. coli and K. pneumoniae). In summary, Ceftaroline showed potent activity against a large contemporary collection (6222) of bacterial isolates associated with ABSSSI in the USA.
Dirk Thye - One of the best experts on this subject based on the ideXlab platform.
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focus 2 a randomized double blinded multicentre phase iii trial of the efficacy and safety of Ceftaroline fosamil versus ceftriaxone in community acquired pneumonia
Journal of Antimicrobial Chemotherapy, 2011Co-Authors: Thomas M File, Paul B Eckburg, George H Talbot, David H Friedland, Lily Llorens, Ian A Critchley, Dirk Thye, Jorge Corral, Eduardo Giugno, Maria Del Rosario Gonzalez ArzacAbstract:Objectives: Ceftaroline (active form of the prodrug Ceftaroline fosamil) is a novel cephalosporin with activity against pathogens commonly associated with community-acquired pneumonia (CAP), including Streptococcus pneumoniae and Gram-negative pathogens. This randomized, double-blind, Phase III study evaluated the efficacy and safety of Ceftaroline fosamil in treating patients with CAP. The primary objective was to determine non-inferiority [lower limit of 95% confidence interval (CI) > ―10%] of clinical cure rates achieved with Ceftaroline fosamil compared with those achieved with ceftriaxone in the clinically evaluable (CE) and modified intent-to-treat efficacy (MITTE) populations. Methods: Patients hospitalized in a non-intensive care unit setting with CAP of Pneumonia Outcomes Research Team (PORT) risk class III or IV requiring intravenous (iv) therapy were randomized (1:1) to receive 600 mg of Ceftaroline fosamil iv every 12 h or 1 g of ceftriaxone iv every 24 h. Clinical cure, microbiological response, adverse events (AEs) and laboratory tests were assessed. FOCUS 2 registration number NCT00509106 (http:// clinicaltrials.gov/ct2/show/NCT00509106). Results: The study enrolled 627 patients, 315 of whom received Ceftaroline fosamil and 307 of whom received ceftriaxone. Patients in both treatment groups had comparable baseline characteristics. Clinical cure rates were as follows: CE population, 82.1% (193/235) for Ceftaroline fosamil and 77.2% (166/215) for ceftriaxone [difference (95% CI), 4.9% (―2.5, 12.5)]; and MITTE population, 81.3% (235/289) for Ceftaroline fosamil and 75.5% (206/273) for ceftriaxone [difference (95% CI), 5.9% (―1.0, 12.7)]. Clinical cure rates for CAP caused by S. pneumoniae in the microbiological MITTE (mMITTE) population were 83.3% (35/42) and 70.0% (28/40) for Ceftaroline fosamil and ceftriaxone, respectively. Ceftaroline fosamil and ceftriaxone were well tolerated, with similar rates of AEs, serious AEs, deaths and discontinuations due to an AE. The most common AEs for Ceftaroline fosamil-treated patients were diarrhoea, headache, hypokalaemia, insomnia and phlebitis, and the most common AEs for ceftriaxone-treated patients were diarrhoea, insomnia, phlebitis and hypertension. Conclusions: Ceftaroline fosamil achieved high clinical cure and microbiological response rates in patients hospitalized with CAP of PORT risk class III or IV. Ceftaroline fosamil was well tolerated, with a safety profile that is similar to that of ceftriaxone and other cephalosporins. Ceftaroline fosamil is a promising agent for the treatment of CAP.
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focus 1 a randomized double blinded multicentre phase iii trial of the efficacy and safety of Ceftaroline fosamil versus ceftriaxone in community acquired pneumonia
Journal of Antimicrobial Chemotherapy, 2011Co-Authors: Thomas M File, Paul B Eckburg, George H Talbot, David H Friedland, Lily Llorens, Ian A Critchley, Dirk Thye, John Pullman, Philip Giordano, James WelkerAbstract:Objectives: Ceftaroline, the active form of the prodrug Ceftaroline fosamil, is a novel cephalosporin with bactericidal activity against important pathogens associated with community-acquired pneumonia (CAP), including Streptococcus pneumoniae and common Gram-negative pathogens. FOCUS 1 is a randomized, double-blinded, Phase III study that was conducted to evaluate the efficacy and safety of Ceftaroline fosamil in treating patients with CAP. The primary objective was to determine non-inferiority [lower limit of 95% confidence interval (CI) ≥ ―10%] in clinical cure rates achieved with Ceftaroline fosamil compared with those achieved with ceftriaxone in the clinically evaluable (CE) and modified intent-to-treat efficacy (MITTE) populations. Methods: Patients hospitalized in a non-intensive care unit setting with CAP of Pneumonia Outcomes Research Team (PORT) risk class III or IV requiring intravenous (iv) therapy were randomized (1:1) to receive 600 mg of Ceftaroline fosamil iv every 12 h or 1 g of ceftriaxone iv every 24 h. Patients also received two 500 mg doses of oral clarithromycin every 12 h administered on day 1. Clinical cure, microbiological response, adverse events (AEs) and laboratory tests were assessed. FOCUS 1 registration number NCT00621504 (http://clinicaltrials.gov/ ct2/show/NCT00621504). Results: Of 613 enrolled patients, 298 received Ceftaroline fosamil and 308 received ceftriaxone. Baseline characteristics between treatment groups were comparable. Clinical cure rates were as follows: CE population, 86.6% (194/224) for Ceftaroline fosamil and 78.2% (183/234) for ceftriaxone [difference (95% CI), 8.4% (1.4, 15.4)]; and MITTE population, 83.8% (244/291) for Ceftaroline fosamil and 77.7% (233/300) for ceftriaxone [difference (95% CI), 6.2% (―0.2, 12.6)]. Clinical cure rates for CAP caused by S. pneumoniae in the microbiological MITTE population were 88.9% (24/27) and 66.7% (20/30) for Ceftaroline fosamil and ceftriaxone, respectively. Both agents were well tolerated, with similar rates of AEs, serious AEs, deaths and discontinuations because of an AE. The most common AEs for Ceftaroline fosamil-treated patients were diarrhoea, headache, insomnia and nausea, and the most common AEs for ceftriaxone-treated patients were hypokalaemia, hypertension, nausea and diarrhoea. Conclusions: Ceftaroline fosamil demonstrated high clinical cure and microbiological response rates in hospitalized patients with CAPof PORT risk class III or IV. Ceftaroline fosamil was well tolerated, with a safety profile similar to that of ceftriaxone and consistent with the cephalosporin class. In this study, Ceftaroline fosamil was an effective and well-tolerated treatment option for CAP.
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review of Ceftaroline fosamil microbiology integrated focus studies
Journal of Antimicrobial Chemotherapy, 2011Co-Authors: Ian A Critchley, Paul B Eckburg, David H Friedland, Donald Biek, Alena Jandourek, Dirk ThyeAbstract:: Ceftaroline fosamil, the prodrug form of Ceftaroline, is a novel broad-spectrum parenteral cephalosporin that exhibits antibacterial activity against typical respiratory pathogens such as Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus and common Gram-negative pathogens. In particular, Ceftaroline has activity against resistant Gram-positive cocci, including penicillin- and multidrug-resistant S. pneumoniae, as well as methicillin-resistant S. aureus. The activity of Ceftaroline against these phenotypes is attributed to its ability to bind to modified penicillin-binding proteins with high affinity when compared with other β-lactams. The activity of Ceftaroline is not compromised by the ability of H. influenzae to produce β-lactamase. Ceftaroline fosamil was compared with ceftriaxone for safety and efficacy in two randomized, double-blinded, controlled Phase III clinical trials for the treatment of community-acquired pneumonia (CAP). Microbiological assessments at baseline included respiratory specimen cultures, blood cultures, urinary antigen testing and atypical pathogen serology testing. By-subject and by-pathogen microbiological outcomes were assessed in the microbiologically evaluable population at the test-of-cure visit. The favourable microbiological response rates by subject for Ceftaroline were 87.0% compared with 81.0% for ceftriaxone. The by-pathogen microbiological response rates of Ceftaroline and ceftriaxone were 87.3% and 72.9% for S. pneumoniae, 83.3% and 85.0% for H. influenzae and 76.0% and 70.4% for S. aureus, respectively. Key baseline pathogens such as S. pneumoniae, H. influenzae and methicillin-susceptible S. aureus were susceptible to Ceftaroline, with MIC(90)s of 0.03, 0.03 and 0.25 mg/L, respectively, supporting its utility as a promising new agent for treatment of CAP.
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integrated analysis of focus 1 and focus 2 randomized doubled blinded multicenter phase 3 trials of the efficacy and safety of Ceftaroline fosamil versus ceftriaxone in patients with community acquired pneumonia
Clinical Infectious Diseases, 2010Co-Authors: Thomas M File, Paul B Eckburg, George H Talbot, David H Friedland, Lily Llorens, Ian A Critchley, Dirk ThyeAbstract:Background Ceftaroline, the active form of Ceftaroline fosamil, is a broad-spectrum cephalosporin with bactericidal activity against pathogens causing community-acquired pneumonia (CAP), including Streptococcus pneumoniae. Ceftaroline was evaluated for the treatment of CAP in 2 randomized, double-blind, multicenter trials: Ceftaroline Community Acquired Pneumonia Trial versus Ceftriaxone in Hospitalized Patients (FOCUS) 1 and FOCUS 2. Methods Patients hospitalized (but not admitted to an intensive care unit) with Pneumonia Outcomes Research Team risk class III or IV CAP requiring intravenous therapy were randomized to Ceftaroline 600 mg every 12 h or ceftriaxone 1 g every 24 h for 5-7 days. Patients in FOCUS 1 received 2 doses of oral clarithromycin 500 mg every 12 h on day 1. Results In the individual trials, clinical cure rates in the clinically evaluable (CE) population for Ceftaroline versus ceftriaxone were as follows: FOCUS 1, 86.6% vs 78.2% (difference, 8.4%; 95% confidence interval [CI], 1.4%-15.4%); FOCUS 2, 82.1% vs 77.2% (difference, 4.9%; 95% CI, -2.5% to 12.5%). In the integrated analysis, 614 patients received Ceftaroline and 614 received ceftriaxone. Of the CE patients treated with Ceftaroline, 84.3% achieved clinical cure, compared with 77.7% of ceftriaxone-treated patients (difference, 6.7%; 95% CI, 1.6%-11.8%). Clinical cure rates in the modified intent-to-treat efficacy population were 82.6% versus 76.6% for Ceftaroline and ceftriaxone (difference, 6.0%; 95% CI, 1.4%-10.7%). Ceftaroline and ceftriaxone were well tolerated; rates of adverse events, serious adverse events, deaths, and premature discontinuations caused by an adverse event were similar in both treatment arms. Conclusions Ceftaroline was noninferior to ceftriaxone in the individual trials. In this integrated analysis, clinical cure rates for the Ceftaroline group were numerically higher than those for the ceftriaxone group. Ceftaroline was well tolerated, with a safety profile similar to that of ceftriaxone.
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Ceftaroline fosamil a novel broad spectrum cephalosporin with expanded anti gram positive activity
Journal of Antimicrobial Chemotherapy, 2010Co-Authors: Donald Biek, Todd Riccobene, Ian A Critchley, Dirk ThyeAbstract:: Ceftaroline fosamil is a novel cephalosporin with broad-spectrum activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Streptococcus pneumoniae, and common Gram-negative organisms. The activity of Ceftaroline against MRSA is attributed to its ability to bind to penicillin-binding protein (PBP) 2a with high affinity and inhibit the biochemical activity of PBP 2a more efficiently than other presently available β-lactams. The activity of Ceftaroline against MRSA and the β-haemolytic streptococci makes it an attractive monotherapy agent for the treatment of complicated skin and skin structure infections (cSSSIs). Recent profiling and surveillance studies have shown that Ceftaroline is active against contemporary skin pathogens collected from US and European medical centres in 2008. The mean free drug %T > MIC (percentage of time the drug concentration remains above the MIC) needed for stasis ranged from 26% for S. aureus to 39% for S. pneumoniae in the murine thigh infection model. Pharmacokinetic and pharmacodynamic target attainment predictions for 600 mg of Ceftaroline fosamil every 12 h showed that the mean %T > MICs for which plasma free-drug concentrations exceeded an MIC of 1 and 2 mg/L were 71% and 51% of the dosing interval, respectively. For a 40% T > MIC target, the predicted attainments for infections due to pathogens for which Ceftaroline MICs were 1 or 2 mg/L were 100% and 90%, respectively. Clinical and microbiological successes of Ceftaroline fosamil in treating cSSSIs were demonstrated in two Phase III clinical studies, in which 96.8% of all baseline cSSSI isolates from the microbiologically evaluable population were inhibited by Ceftaroline at ≤ 2 mg/L. Ceftaroline fosamil is a promising broad-spectrum agent for the treatment of cSSSIs.
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methicillin resistant staphylococcus aureus bacteraemia and endocarditis treated with Ceftaroline salvage therapy
Journal of Antimicrobial Chemotherapy, 2012Co-Authors: Tony T Ho, Jose Cadena, Lindsey M Childs, Miguel Gonzalezvelez, James S LewisAbstract:Background One of the newest methicillin-resistant Staphylococcus aureus (MRSA) antibiotics to receive FDA approval is Ceftaroline fosamil, a member of a new subclass of cephalosporins with unique activity against MRSA. However, Ceftaroline is currently only FDA approved for complicated skin/soft tissue infections and community-acquired pneumonia; there are currently no clinical data regarding its use in MRSA bacteraemia and endocarditis. We report a series of six patients in which Ceftaroline was utilized as salvage monotherapy in persistent MRSA bacteraemia or endocarditis. Methods Using pharmacy records, 11 Ceftaroline-treated patients were identified between January 2011 and November 2011 at University Health System and the South Texas Veterans Health Care System in San Antonio, TX, USA. All cases were reviewed and six patients received Ceftaroline therapy for MRSA bacteraemia or endocarditis due to persistent or recurrent bacteraemia while on standard antibiotics (vancomycin or daptomycin). Results All six patients experienced rapid clearance of their bacteraemia after starting Ceftaroline. In the case of endocarditis for which the patient subsequently developed heart failure and required valve replacement, there was no evidence of growth from cultures taken from the excised valve, suggesting sterilization within 13 days of starting Ceftaroline. Conclusions Ceftaroline exhibits potent anti-MRSA activity in both in vitro and animal studies, including rabbit endocarditis models; however, the lack of clinical data has limited its use in bacteraemia and endovascular infections in humans. We hope that this series serves as an initial stepping stone for further evaluation of this compound for more invasive infections due to MRSA.