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Karen Bush - One of the best experts on this subject based on the ideXlab platform.
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Effects of Ceftobiprole and oxacillin on mecA expression in methicillin-resistant Staphylococcus aureus clinical isolates
2016Co-Authors: Wenchi Shang, Todd A Davies, Robert K Flamm, Karen BushAbstract:Induction of mecA by Ceftobiprole and oxacillin in 18 methicillin-resistant Staphylococcus aureus clinical isolates with various SCCmec cassettes was examined using reverse transcriptase PCR. The magnitude of mecA induction, 3- to 65-fold for Ceftobiprole and 2- to 69-fold for oxacillin, did not correlate with Ceftobiprole MICs (<4 g/ml), although the 11 isolates with at least 13-fold induction by oxacillin all had oxacillin MICs of>256 g/ml. No correlation between magnitude of induction and SCCmec type was found. Ceftobiprole is a cephalosporin with a broad spectrum of activity against many Gram-negative and Gram-positive pathogens including methicillin-resistant Staphylococcus au-reus (MRSA) (14). It is currently under regulatory review in the United States and has been approved in several other countries for the treatment of complicated skin and skin structure infections (cSSSI). The major mechanism of methicillin resistance in S. au-reus is the acquisition and expression of the mecA gene that encodes penicillin-binding protein 2a (PBP2a) (12, 23). Un
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differential selection of single step ampc or efflux mutants of pseudomonas aeruginosa by using cefepime ceftazidime or Ceftobiprole
Antimicrobial Agents and Chemotherapy, 2010Co-Authors: Anne Marie Queenan, Wenchi Shang, Karen Bush, Robert K FlammAbstract:Single-step Pseudomonas aeruginosa mutants, selected with Ceftobiprole, ceftazidime, or cefepime, were generated at frequencies of 10−6 to <10−9 at two and four times the MIC. The chromosomal AmpC β-lactamase activity was increased in all ceftazidime-selected mutants. Mutants selected with cefepime either increased AmpC activity or upregulated expression of the mexXY efflux genes. Mutants selected with Ceftobiprole did not overexpress AmpC; 90% of these produced elevated levels of mexXY RNA, indicating that increased efflux, not AmpC derepression, is the predominant response to Ceftobiprole during first-step mutations in P. aeruginosa.
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effects of Ceftobiprole and oxacillin on meca expression in methicillin resistant staphylococcus aureus clinical isolates
Antimicrobial Agents and Chemotherapy, 2010Co-Authors: Wenchi Shang, Todd A Davies, Robert K Flamm, Karen BushAbstract:Induction of mecA by Ceftobiprole and oxacillin in 18 methicillin-resistant Staphylococcus aureus clinical isolates with various SCCmec cassettes was examined using reverse transcriptase PCR. The magnitude of mecA induction, 3- to 65-fold for Ceftobiprole and 2- to 69-fold for oxacillin, did not correlate with Ceftobiprole MICs (≤4 μg/ml), although the 11 isolates with at least 13-fold induction by oxacillin all had oxacillin MICs of ≥256 μg/ml. No correlation between magnitude of induction and SCCmec type was found.
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effect of mexxy overexpression on Ceftobiprole susceptibility in pseudomonas aeruginosa
Antimicrobial Agents and Chemotherapy, 2009Co-Authors: Ellen Z Baum, Todd A Davies, Anne Marie Queenan, Steven M Crespocarbone, Brian J Morrow, Barbara D Foleno, Karen BushAbstract:Ceftobiprole, an anti-methicillin-resistant Staphylococcus aureus broad-spectrum cephalosporin, has activity (MIC for 50% of strains tested, < or =4 microg/ml) against many Pseudomonas aeruginosa strains. A common mechanism of P. aeruginosa resistance to beta-lactams, including cefepime and ceftazidime, is efflux via increased expression of Mex pumps, especially MexAB. MexXY has differential substrate specificity, recognizing cefepime but not ceftazidime. In Ceftobiprole clinical studies, paired isolates of P. aeruginosa from four subjects demonstrated Ceftobiprole MICs of 2 to 4 microg/ml at baseline but 16 microg/ml posttreatment, unrelated to beta-lactamase levels. Within each pair, the level of mexXY RNA, but not mexAB, mexCD, and mexEF, increased by an average of 50-fold from baseline to posttreatment isolates. Sequencing of the negative regulatory gene mexZ indicated that each posttreatment isolate contained a mutation not present at baseline. mexXY expression as a primary Ceftobiprole and cefepime resistance mechanism was further examined in isogenic pairs by using cloned mexXY and mexZ. Expression of cloned mexXY in strain PAO1 or in a baseline isolate increased the Ceftobiprole MIC to that for the posttreatment isolate. In contrast, in posttreatment isolates, lowering mexXY expression via introduction of cloned mexZ decreased the Ceftobiprole MIC to that for the baseline isolates. Similar changes were observed for cefepime. A spontaneous mutant selectively overexpressing mexXY displayed a fourfold elevation in its Ceftobiprole MIC, while overexpression of mexAB, -CD, and -EF had a minimal effect. These data indicate that Ceftobiprole, like cefepime, is an atypical beta-lactam that is a substrate for the MexXY efflux pump in P. aeruginosa.
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in vitro activity of Ceftobiprole against pathogens from two phase 3 clinical trials of complicated skin and skin structure infections
Antimicrobial Agents and Chemotherapy, 2008Co-Authors: K Amsler, Wenchi Shang, Todd A Davies, Michael R Jacobs, Karen BushAbstract:In phase 3 clinical trials for Ceftobiprole treatment of complicated skin and skin structure infections, 1,219 gram-positive and 276 gram-negative aerobic baseline pathogens were identified. Ceftobiprole inhibited all staphylococcal isolates, including methicillin-resistant strains, at MICs of ≤4 μg/ml. Against Enterobacteriaceae and Pseudomonas aeruginosa isolates, the potency of Ceftobiprole was similar to that of cefepime.
Michael J Rybak - One of the best experts on this subject based on the ideXlab platform.
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Ceftobiprole and ampicillin increase daptomycin susceptibility of daptomycin susceptible and resistant vre
Journal of Antimicrobial Chemotherapy, 2015Co-Authors: Brian J Werth, Katie E Barber, Poochit Nonejuie, George Sakoulas, Joe Pogliano, Michael J Rybak, Kieu Nhi T TranAbstract:OBJECTIVES The synergistic combination of daptomycin plus ampicillin has proven to be effective against VRE including daptomycin-non-susceptible strains. Ceftobiprole is a cephalosporin with broad binding affinity for enterococcal PBP subtypes including PBP5. Given the synergy between β-lactams and daptomycin against VRE, it was of interest to determine whether Ceftobiprole offered any synergistic advantage with daptomycin compared with ampicillin. METHODS MICs were determined by broth microdilution in the presence and absence of ampicillin or Ceftobiprole for 20 ampicillin-resistant VRE. Six strains, including two isogenic pairs of vancomycin-resistant Enterococcus faecium and two vancomycin-resistant Enterococcus faecalis, were evaluated for synergy using time-kill methods. Synergy was defined as a ≥2 log10 cfu/mL reduction of the combination over the most active single agent. Binding of daptomycin-bodipy in the presence and absence of Ceftobiprole was quantified. RESULTS Daptomycin MICs ranged from 2 to 256 mg/L. The addition of Ceftobiprole and ampicillin reduced daptomycin MICs by a median of 3 and 4 log2 dilutions, respectively. In time-kill studies, daptomycin plus either Ceftobiprole or ampicillin was synergistic against four of six strains, but not the same strains. Both combinations were synergistic against the vancomycin-resistant E. faecalis strains. Ceftobiprole exposure increased daptomycin-bodipy binding by 2.8 times (P<0.0001). CONCLUSIONS Ceftobiprole appears to offer a similar degree of synergistic activity to ampicillin when combined with daptomycin against VRE. Further research should explore the genetic and phenotypic qualities of strains that respond preferentially to Ceftobiprole as opposed to ampicillin.
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potent synergy of Ceftobiprole plus daptomycin against multiple strains of staphylococcus aureus with various resistance phenotypes
Journal of Antimicrobial Chemotherapy, 2014Co-Authors: Katie E Barber, Brian J Werth, Cortney E Ireland, Nicole E Stone, Poochit Nonejuie, George Sakoulas, Joe Pogliano, Michael J RybakAbstract:Objectives: Ceftobiprole is a broad-spectrum cephalosporin that demonstrates activity against Staphylococcus aureus resistant to methicillin, including strains with reduced susceptibility to glycopeptides and lipopeptides. The addition of this agent provides a potential therapeutic option for difficult-to-treat infections. Synergy has been demonstrated between b-lactams combined with glycopeptides and lipopeptides against S. aureus. This study sought to determine whether Ceftobiprole was synergistic with daptomycin, vancomycin or standard-of-care combination agents (gentamicin or rifampicin) against methicillin-resistant S. aureus (MRSA) strains with varying degrees of vancomycin susceptibility. Methods: Broth microdilution MICs of Ceftobiprole, daptomycin, vancomycin, rifampicin and gentamicin were evaluated for 20 MRSA isolates. Combination MICs were additionally evaluated in the presence of subinhibitory concentrations of Ceftobiprole to assess synergism. Time – kill curves for five representative isolates were performed utilizing combinations of Ceftobiprole plus daptomycin, vancomycin, rifampicin and gentamicin to further quantify the degree of synergy for each regimen. Results: Ceftobiprole plus daptomycin represented the most potent combination with a 4-fold decrease in MIC and synergy against all strains evaluated in time– kill evaluations. Additionally, binding studies demonstrated enhanced daptomycin binding in the presence of subinhibitory concentrations of Ceftobiprole. Conclusions: The use of combination therapy with Ceftobiprole may provide a needed addition for the treatment of Gram-positive infections resistant to daptomycin or vancomycin. Consistent with what has been observed with other b-lactams, Ceftobiprole increased bodipy-tagged daptomycin binding on the surface of S. aureus, potentially explaining this potent synergy observed in time – kill evaluations. More detailed evaluation of Ceftobiprole is warranted to better characterize observed synergy.
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Ceftobiprole first cephalosporin with activity against methicillin resistant staphylococcus aureus
Pharmacotherapy, 2009Co-Authors: Celine Vidaillac, Michael J RybakAbstract:Ceftobiprole medocaril is the first member of a new series of advanced cephalosporins with activity against methicillin-resistant Staphylococcus aureus (MRSA). The drug received an approvable letter from the United States Food and Drug Administration (FDA) in March 2008 and from Health Canada in June 2008 for the treatment of complicated skin and skin structure infections including diabetic foot infections. Ceftobiprole exerts its antibacterial activity by inhibiting the penicillin-binding proteins (PBPs) involved in cell wall synthesis. It has an established stability against hydrolysis by many gram-positive beta-lactamases and a higher affinity for various PBPs (such as PBP2a of MRSA or PBP2x of Streptococcus pneumoniae), which leads to a wider spectrum of activity compared with older beta-lactams. Ceftobiprole activity does not cover extended-spectrum beta-lactamase-producing Enterobacteriaceae and some other pathogens, including Enterococcus faecium or Acinetobacter baumanii. Generally well tolerated, with nausea and taste disturbance being the most common adverse events, Ceftobiprole appeared noninferior to empiric therapy in several clinical trials. Ceftobiprole is available only for intravenous administration; recommended dosage regimens have not been approved by the FDA as of this writing. However, based on the Canadian package insert, expected dosage recommendations are 500 mg as a 1-hour intravenous infusion every 12 hours for the treatment of complicated skin and skin structure infections caused by certain gram-positive pathogens, and 500 mg as a 2-hour infusion every 8 hours when susceptible gram-negative or both gram-positive and susceptible gram-negative pathogens are involved. Dosage adjustments are indicated for patients with moderate or severe renal impairment, and dosage recommendations are expected to be 500 or 250 mg, respectively, as a 2-hour infusion every 12 hours. Several precautions regarding hypersensitivity and drug incompatibility are reported. Ceftobiprole represents a promising option for the treatment of mono- and polymicrobial infections caused by multidrug-resistant gram-positive and susceptible gram-negative pathogens, but further toxicity and safety studies are warranted.
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activities of Ceftobiprole linezolid vancomycin and daptomycin against community associated and hospital associated methicillin resistant staphylococcus aureus
Antimicrobial Agents and Chemotherapy, 2008Co-Authors: Michael J Rybak, Steven N Leonard, Chrissy M CheungAbstract:We evaluated the activity of Ceftobiprole against 100 community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) and 100 hospital-associated MRSA (HA-MRSA) isolates. Eight isolates were evaluated by time-kill studies for kill rate and potential for synergy with tobramycin. Ceftobiprole MIC50 and MIC90 values were 1 and 2 g/ml, respectively, against CA-MRSA and HA-MRSA. In time-kill analysis, Ceftobiprole was bactericidal at all concentrations tested.
Todd A Davies - One of the best experts on this subject based on the ideXlab platform.
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Effects of Ceftobiprole and oxacillin on mecA expression in methicillin-resistant Staphylococcus aureus clinical isolates
2016Co-Authors: Wenchi Shang, Todd A Davies, Robert K Flamm, Karen BushAbstract:Induction of mecA by Ceftobiprole and oxacillin in 18 methicillin-resistant Staphylococcus aureus clinical isolates with various SCCmec cassettes was examined using reverse transcriptase PCR. The magnitude of mecA induction, 3- to 65-fold for Ceftobiprole and 2- to 69-fold for oxacillin, did not correlate with Ceftobiprole MICs (<4 g/ml), although the 11 isolates with at least 13-fold induction by oxacillin all had oxacillin MICs of>256 g/ml. No correlation between magnitude of induction and SCCmec type was found. Ceftobiprole is a cephalosporin with a broad spectrum of activity against many Gram-negative and Gram-positive pathogens including methicillin-resistant Staphylococcus au-reus (MRSA) (14). It is currently under regulatory review in the United States and has been approved in several other countries for the treatment of complicated skin and skin structure infections (cSSSI). The major mechanism of methicillin resistance in S. au-reus is the acquisition and expression of the mecA gene that encodes penicillin-binding protein 2a (PBP2a) (12, 23). Un
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in vitro activities of Ceftobiprole combined with amikacin or levofloxacin against pseudomonas aeruginosa evidence of a synergistic effect using time kill methodology
International Journal of Antimicrobial Agents, 2011Co-Authors: Michael Kresken, Jorg M Lauffer, Barbara Korberirrgang, Sabine Deckerburgard, Todd A DaviesAbstract:Ceftobiprole is an investigational intravenous broad-spectrum cephalosporin with in vitro activity against Gram-positive and Gram-negative pathogens, including meticillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa. Pseudomonas aeruginosa is a frequent nosocomial pathogen, increasingly associated with complicated skin and skin-structure infections. Combination antimicrobial therapy is recommended as empirical therapy for serious infections where P. aeruginosa is suspected. Therefore, in this study the interaction of Ceftobiprole with two other antipseudomonal agents (amikacin and levofloxacin) was investigated. Time-kill studies were performed for each single agent and for the combination of Ceftobiprole 4 mg/L with either amikacin or levofloxacin at 0.5×, 1× and 2× the minimum inhibitory concentration. Five clinical isolates of P. aeruginosa as well as the P. aeruginosa ATCC 27853 reference strain were tested at initial inocula of 5×10(5) colony-forming units (CFU)/mL (low inoculum) or 5×10(7) CFU/mL (high inoculum). Synergy was defined as a decrease of ≥2log(10) CFU/mL with the combination compared with the most active single drug at 6 h and 24 h. At low inoculum with Ceftobiprole as a single agent, viable counts were decreased by 1.5-2log(10) at 6 h. Addition of either amikacin or levofloxacin resulted in synergistic bactericidal activity at 24 h. At high inoculum the combination of Ceftobiprole with amikacin or levofloxacin demonstrated synergism in one of three and three of five strains, respectively. This study demonstrated that the combination of Ceftobiprole at a clinically achievable concentration of 4 mg/L with amikacin or levofloxacin exhibited synergistic activity against P. aeruginosa. There was no evidence of antagonism for either combination.
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effects of Ceftobiprole and oxacillin on meca expression in methicillin resistant staphylococcus aureus clinical isolates
Antimicrobial Agents and Chemotherapy, 2010Co-Authors: Wenchi Shang, Todd A Davies, Robert K Flamm, Karen BushAbstract:Induction of mecA by Ceftobiprole and oxacillin in 18 methicillin-resistant Staphylococcus aureus clinical isolates with various SCCmec cassettes was examined using reverse transcriptase PCR. The magnitude of mecA induction, 3- to 65-fold for Ceftobiprole and 2- to 69-fold for oxacillin, did not correlate with Ceftobiprole MICs (≤4 μg/ml), although the 11 isolates with at least 13-fold induction by oxacillin all had oxacillin MICs of ≥256 μg/ml. No correlation between magnitude of induction and SCCmec type was found.
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effect of mexxy overexpression on Ceftobiprole susceptibility in pseudomonas aeruginosa
Antimicrobial Agents and Chemotherapy, 2009Co-Authors: Ellen Z Baum, Todd A Davies, Anne Marie Queenan, Steven M Crespocarbone, Brian J Morrow, Barbara D Foleno, Karen BushAbstract:Ceftobiprole, an anti-methicillin-resistant Staphylococcus aureus broad-spectrum cephalosporin, has activity (MIC for 50% of strains tested, < or =4 microg/ml) against many Pseudomonas aeruginosa strains. A common mechanism of P. aeruginosa resistance to beta-lactams, including cefepime and ceftazidime, is efflux via increased expression of Mex pumps, especially MexAB. MexXY has differential substrate specificity, recognizing cefepime but not ceftazidime. In Ceftobiprole clinical studies, paired isolates of P. aeruginosa from four subjects demonstrated Ceftobiprole MICs of 2 to 4 microg/ml at baseline but 16 microg/ml posttreatment, unrelated to beta-lactamase levels. Within each pair, the level of mexXY RNA, but not mexAB, mexCD, and mexEF, increased by an average of 50-fold from baseline to posttreatment isolates. Sequencing of the negative regulatory gene mexZ indicated that each posttreatment isolate contained a mutation not present at baseline. mexXY expression as a primary Ceftobiprole and cefepime resistance mechanism was further examined in isogenic pairs by using cloned mexXY and mexZ. Expression of cloned mexXY in strain PAO1 or in a baseline isolate increased the Ceftobiprole MIC to that for the posttreatment isolate. In contrast, in posttreatment isolates, lowering mexXY expression via introduction of cloned mexZ decreased the Ceftobiprole MIC to that for the baseline isolates. Similar changes were observed for cefepime. A spontaneous mutant selectively overexpressing mexXY displayed a fourfold elevation in its Ceftobiprole MIC, while overexpression of mexAB, -CD, and -EF had a minimal effect. These data indicate that Ceftobiprole, like cefepime, is an atypical beta-lactam that is a substrate for the MexXY efflux pump in P. aeruginosa.
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in vitro activity of Ceftobiprole against pathogens from two phase 3 clinical trials of complicated skin and skin structure infections
Antimicrobial Agents and Chemotherapy, 2008Co-Authors: K Amsler, Wenchi Shang, Todd A Davies, Michael R Jacobs, Karen BushAbstract:In phase 3 clinical trials for Ceftobiprole treatment of complicated skin and skin structure infections, 1,219 gram-positive and 276 gram-negative aerobic baseline pathogens were identified. Ceftobiprole inhibited all staphylococcal isolates, including methicillin-resistant strains, at MICs of ≤4 μg/ml. Against Enterobacteriaceae and Pseudomonas aeruginosa isolates, the potency of Ceftobiprole was similar to that of cefepime.
Mikael Saulay - One of the best experts on this subject based on the ideXlab platform.
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a post hoc analysis of two phase iii trials showing the efficacy and tolerability of Ceftobiprole in east asian patients
Future Microbiology, 2021Co-Authors: Haihui Huang, Marc Engelhardt, Mikael Saulay, Lei Gao, Kamal HamedAbstract:Aim: To evaluate the efficacy and safety of Ceftobiprole in patients from East Asia. Materials & methods: A post hoc analysis was conducted of two randomized, double-blind, Phase III studies in patients with community- or hospital-acquired pneumonia. Results: Findings for East Asian patients were consistent with the overall study populations. A trend toward higher microbiological eradication rates and numerically lower rates of all-cause mortality were reported for Ceftobiprole versus comparators (all-cause mortality [intent-to-treat]: community-acquired pneumonia, 1.5 vs 2.8%; hospital-acquired pneumonia excluding ventilator-associated pneumonia, 5.9 vs 11.4%). The incidence of adverse events was similar between treatment groups. Conclusion: This post hoc analysis supports the efficacy and tolerability of Ceftobiprole in East Asian patients. ClinicalTrials.gov trial identifiers: NCT00326287, NCT00210964, NCT00229008.
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Ceftobiprole compared with vancomycin plus aztreonam in the treatment of acute bacterial skin and skin structure infections results of a phase 3 randomized double blind trial target
Clinical Infectious Diseases, 2020Co-Authors: Scott J Overcash, Charles Kim, Richard Keech, Illia Gumenchuk, Borislav Ninov, Yaneicy Gonzalezrojas, Michael Waters, Simeon B Simeonov, Marc Engelhardt, Mikael SaulayAbstract:Background The development of novel broad-spectrum antibiotics, with efficacy against both gram-positive and gram-negative bacteria, has the potential to enhance treatment options for acute bacterial skin and skin structure infections (ABSSSIs). Ceftobiprole is an advanced-generation intravenous cephalosporin with broad in vitro activity against gram-positive (including methicillin-resistant Staphylococcus aureus) and gram-negative pathogens. Methods TARGET was a randomized, double-blind, active-controlled, parallel-group, multicenter, phase 3 noninferiority study that compared Ceftobiprole with vancomycin plus aztreonam. The Food and Drug Administration-defined primary efficacy endpoint was early clinical response 48-72 hours after treatment initiation in the intent-to-treat (ITT) population and the European Medicines Agency-defined primary endpoint was investigator-assessed clinical success at the test-of-cure (TOC) visit. Noninferiority was defined as the lower limit of the 95% CI for the difference in success rates (Ceftobiprole minus vancomycin/aztreonam) >-10%. Safety was assessed through adverse event and laboratory data collection. Results In total, 679 patients were randomized to Ceftobiprole (n = 335) or vancomycin/aztreonam (n = 344). Early clinical success rates were 91.3% and 88.1% in the Ceftobiprole and vancomycin/aztreonam groups, respectively, and noninferiority was demonstrated (adjusted difference: 3.3%; 95% CI: -1.2, 7.8). Investigator-assessed clinical success at the TOC visit was similar between the 2 groups, and noninferiority was demonstrated for both the ITT (90.1% vs 89.0%) and clinically evaluable (97.9% vs 95.2%) populations. Both treatment groups displayed similar microbiological success and safety profiles. Conclusions TARGET demonstrated that Ceftobiprole is noninferior to vancomycin/aztreonam in the treatment of ABSSSIs, in terms of early clinical response and investigator-assessed clinical success at the TOC visit. Clinical trials registration NCT03137173.
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a phase 3 randomized double blind comparison of Ceftobiprole medocaril versus ceftazidime plus linezolid for the treatment of hospital acquired pneumonia
Clinical Infectious Diseases, 2014Co-Authors: Samir S Awad, Thomas Scheeren, Alejandro Rodriguez, Yinching Chuang, Zsuszanna Marjanek, Alex J Pareigis, Gilmar Reis, A Sanchez, Xin Zhou, Mikael SaulayAbstract:Background: Ceftobiprole, the active moiety of Ceftobiprole medocaril, is a novel broad-spectrum cephalosporin, with bactericidal activity against a wide range of gram-positive bacteria, including Staphylococcus aureus (including methicillin-resistant strains) and penicillin-and ceftriaxone-resistant pneumococci, and gram-negative bacteria, including Enterobacteriaceae and Pseudomonas aeruginosa. Methods: This was a double-blind, randomized, multicenter study of 781 patients with hospital-acquired pneumonia (HAP), including 210 with ventilator-associated pneumonia (VAP). Treatment was intravenous Ceftobiprole 500 mg every 8 hours, or ceftazidime 2 g every 8 hours plus linezolid 600 mg every 12 hours; primary outcome was clinical cure at the test-of-cure visit. Results: Overall cure rates for Ceftobiprole vs ceftazidime/linezolid were 49.9% vs 52.8% (intent-to-treat [ITT], 95% confidence interval [CI] for the difference, -10.0 to 4.1) and 69.3% vs 71.3% (clinically evaluable [CE], 95% CI, -10.0 to 6.1). Cure rates in HAP (excluding VAP) patients were 59.6% vs 58.8% (ITT, 95% CI, -7.3 to 8.8), and 77.8% vs 76.2% (CE, 95% CI, -6.9 to 10.0). Cure rates in VAP patients were 23.1% vs 36.8% (ITT, 95% CI, -26.0 to -1.5) and 37.7% vs 55.9% (CE, 95% CI, -36.4 to 0). Microbiological eradication rates in HAP (excluding VAP) patients were, respectively, 62.9% vs 67.5% (microbiologically evaluable [ME], 95% CI, -16.7 to 7.6), and in VAP patients 30.4% vs 50.0% (ME, 95% CI, -38.8 to -0.4). Treatment-related adverse events were comparable for Ceftobiprole (24.9%) and ceftazidime/linezolid (25.4%). Conclusions: Ceftobiprole is a safe and effective bactericidal antibiotic for the empiric treatment of HAP (excluding VAP). Further investigations are needed before recommending the use of Ceftobiprole in VAP patients.
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a phase 3 randomized double blind comparison of Ceftobiprole medocaril versus ceftazidime plus linezolid for the treatment of hospital acquired pneumonia
Clinical Infectious Diseases, 2014Co-Authors: Samir S Awad, Thomas Scheeren, Alejandro Rodriguez, Yinching Chuang, Zsuszanna Marjanek, Alex J Pareigis, Gilmar Reis, Xin Zhou, Alejandro S Sanchez, Mikael SaulayAbstract:Background. Ceftobiprole, the active moiety of Ceftobiprole medocaril, is a novel broad-spectrum cephalosporin, with bactericidal activity against a wide range of gram-positive bacteria, including Staphylococcus aureus (including methicillin-resistant strains) and penicillin- and ceftriaxone-resistant pneumococci, and gram-negative bacteria, including Enterobacteriaceae and Pseudomonas aeruginosa. Methods. This was a double-blind, randomized, multicenter study of 781 patients with hospital-acquired pneumonia (HAP), including 210 with ventilator-associated pneumonia (VAP). Treatment was intravenous Ceftobiprole 500 mg every 8 hours, or ceftazidime 2 g every 8 hours plus linezolid 600 mg every 12 hours; primary outcome was clinical cure at the test-of-cure visit. Results. Overall cure rates for Ceftobiprole vs ceftazidime/linezolid were 49.9% vs 52.8% (intent-to-treat [ITT], 95% confidence interval [CI] for the difference, −10.0 to 4.1) and 69.3% vs 71.3% (clinically evaluable [CE], 95% CI, −10.0 to 6.1). Cure rates in HAP (excluding VAP) patients were 59.6% vs 58.8% (ITT, 95% CI, −7.3 to 8.8), and 77.8% vs 76.2% (CE, 95% CI, −6.9 to 10.0). Cure rates in VAP patients were 23.1% vs 36.8% (ITT, 95% CI, −26.0 to −1.5) and 37.7% vs 55.9% (CE, 95% CI, −36.4 to 0). Microbiological eradication rates in HAP (excluding VAP) patients were, respectively, 62.9% vs 67.5% (microbiologically evaluable [ME], 95% CI, −16.7 to 7.6), and in VAP patients 30.4% vs 50.0% (ME, 95% CI, −38.8 to −0.4). Treatment-related adverse events were comparable for Ceftobiprole (24.9%) and ceftazidime/linezolid (25.4%). Conclusions. Ceftobiprole is a safe and effective bactericidal antibiotic for the empiric treatment of HAP (excluding VAP). Further investigations are needed before recommending the use of Ceftobiprole in VAP patients. Clinical Trials Registration. {"type":"clinical-trial","attrs":{"text":"NCT00210964","term_id":"NCT00210964"}}NCT00210964, {"type":"clinical-trial","attrs":{"text":"NCT00229008","term_id":"NCT00229008"}}NCT00229008.
George G Zhanel - One of the best experts on this subject based on the ideXlab platform.
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real life experience with Ceftobiprole in canada results from the clear canadianleadership onantimicrobialreal life usage registry
Journal of global antimicrobial resistance, 2021Co-Authors: George G Zhanel, Justin Kosar, Melanie R Baxter, Rita Dhami, Sergio Borgia, Neal Irfan, Kelly S Macdonald, Gordon Dow, Philippe Lagacewiens, Maxime DubeAbstract:Objectives Ceftobiprole is an advanced-generation cephalosporin with a favorable safety profile. Published data on the clinical use of Ceftobiprole are limited. We report the use of Ceftobiprole in Canadian patients using data captured by the CLEAR registry. Methods The CLEAR registry uses the web-based research data management program, REDCapTM (online survey, https://is.gd/CLEARCeftobiprole) to facilitate clinicians entering details associated with their clinical experiences using Ceftobiprole. Results Data were available for 38 patients treated with Ceftobiprole. The most common infections treated were endocarditis (42.1% of patients), bone/joint infection (23.7%), and hospital-associated bacterial pneumonia (15.8%). 92.1% of patients had bacteremia and 21.1% were in intensive care. Ceftobiprole was used because of failure of (71.1%), resistance to (18.4%), or adverse effects from (10.5%) previously prescribed antimicrobial agents. Ceftobiprole was primarily used as directed therapy for methicillin-resistant Staphylococcus aureus-MRSA infections (94.7% of patients). Ceftobiprole susceptibility testing was performed in isolates from 47.4% of patients. It was used concomitantly with daptomycin in 55.3% of patients and with vancomycin in 18.4% of patients. Treatment duration was primarily >10 days (65.8% of patients) with microbiological success in 97.0% and clinical success in 84.8% of patients. 2.6% of patients had gastrointestinal adverse effects. Conclusions In Canada to date, Ceftobiprole is used as directed therapy to treat a variety of severe infections caused by MRSA. It is primarily used in patients failing previous antimicrobials, is frequently added to, and thus used in combination with daptomycin or vancomycin with high microbiological and clinical cure rates, along with an excellent safety profile.
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real life experience with Ceftobiprole in canada results from the clear canadianleadership onantimicrobialreal life usage registry
Journal of global antimicrobial resistance, 2021Co-Authors: George G Zhanel, Justin Kosar, Melanie R Baxter, Rita Dhami, Sergio Borgia, Neal Irfan, Kelly S Macdonald, Gordon Dow, Philippe Lagacewiens, Maxime DubeAbstract:Abstract Objectives Ceftobiprole is an advanced-generation cephalosporin with a favourable safety profile. Published data on the clinical use of Ceftobiprole are limited. We report use of Ceftobiprole in Canadian patients using data captured by the CLEAR registry. Methods The CLEAR registry uses the web-based research data management program REDCap™ (online survey) to facilitate clinicians entering details associated with their clinical experiences using Ceftobiprole. Results Data were available for 38 patients treated with Ceftobiprole. The most common infections treated were endocarditis (42.1% of patients), bone and joint infection (23.7%) and hospital-associated bacterial pneumonia (15.8%). 92.1% of patients had bacteraemia and 21.1% were in intensive care. Ceftobiprole was used because of failure of (71.1%), resistance to (18.4%) or adverse effects from (10.5%) previously prescribed antimicrobial agents. Ceftobiprole was primarily used as directed therapy for methicillin-resistant Staphylococcus aureus (MRSA) infections (94.7% of patients). Ceftobiprole susceptibility testing was performed on isolates from 47.4% of patients. It was used concomitantly with daptomycin in 55.3% of patients and with vancomycin in 18.4% of patients. Treatment duration was primarily >10 days (65.8% of patients) with microbiological success in 97.0% and clinical success in 84.8% of patients. 2.6% of patients had gastrointestinal adverse effects. Conclusion In Canada to date, Ceftobiprole is used as directed therapy to treat a variety of severe infections caused by MRSA. It is primarily used in patients failing previous antimicrobials, is frequently added to, and thus used in combination with daptomycin or vancomycin with high microbiological and clinical cure rates and an excellent safety profile.
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in vitro activity of Ceftobiprole against frequently encountered aerobic and facultative gram positive and gram negative bacterial pathogens results of the canward 2007 2009 study
Diagnostic Microbiology and Infectious Disease, 2011Co-Authors: Andrew Walkty, Daryl J Hoban, James A Karlowsky, Heather J Adam, Michel Laverdiere, George G ZhanelAbstract:Abstract The in vitro activity of Ceftobiprole was evaluated against 15 011 clinical isolates obtained from patients in Canadian hospitals between 2007 and 2009. All Staphylococcus aureus were susceptible to Ceftobiprole (MIC 90 ′s for methicillin-susceptible Staphylococcus aureus and methicillin-resistant Staphylococcus aureus of ≤1 μg/mL and 2 μg/mL, respectively). Ceftobiprole was active against penicillin-susceptible Streptococcus pneumoniae (MIC 90 , ≤0.06 μg/mL), penicillin-resistant Streptococcus pneumoniae (MIC 90 , 0.5 μg/mL), Streptococcus pyogenes (MIC 90 , ≤0.06 μg/mL), Staphylococcus epidermidis (MIC 90 , ≤1 μg/mL), and Enterococcus faecalis (MIC 90 , ≤1 μg/mL). Over 90% of Escherichia coli , Klebsiella pneumoniae , Enterobacter aerogenes , Citrobacter freundii , Proteus mirabilis , and Serratia marcescens isolates were inhibited by a Ceftobiprole concentration of ≤1 μg/mL. Ceftobiprole was not active against extended-spectrum β-lactamase–producing Escherichia coli and K. pneumoniae . The in vitro activity of Ceftobiprole versus Pseudomonas aeruginosa was similar to that of cefepime (MIC 90 , 16 μg/mL). The broad spectrum of activity by Ceftobiprole would support further study of this agent in the treatment of hospital-acquired infections.
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pharmacodynamic activity of Ceftobiprole compared with vancomycin versus methicillin resistant staphylococcus aureus mrsa vancomycin intermediate staphylococcus aureus visa and vancomycin resistant staphylococcus aureus vrsa using an in vitro model
Journal of Antimicrobial Chemotherapy, 2009Co-Authors: George G Zhanel, Ayman M Noreddin, James A Karlowsky, Kim Nichol, Dylan Voth, Daryl J HobanAbstract:Background This study compared the pharmacodynamics of Ceftobiprole and vancomycin against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA) using an in vitro model. Methods Two methicillin-susceptible S. aureus (MSSA), two community-associated (CA)-MRSA, one healthcare-associated (HA)-MRSA, three VISA and two VRSA were studied. The pharmacodynamic model was inoculated with a concentration of 1 x 10(6) cfu/mL and Ceftobiprole dosed every 8 h (at 0, 8 and 16 h) to simulate the fC(max) and t(1/2) obtained after 500 mg intravenous (iv) every 8 h dosing (fC(max,) 30 mg/L; t(1/2,) 3.5 h). Vancomycin was dosed every 12 h (at 0 and 12 h) to simulate fC(max) and t(1/2) obtained after 1 g iv every 12 h dosing (fC(max), 20 mg/L; t(1/2), 8 h). Samples were collected over 24 h to assess viable growth. Results Ceftobiprole T > MIC of > or =100% (Ceftobiprole MICs, or =3 log(10) killing) against MSSA, CA-MRSA, HA-MRSA, VISA and VRSA at 16 and 24 h. Vancomycin fAUC(24)/MIC of 340 (vancomycin MIC, 1 mg/L for MSSA and MRSA) resulted in a 1.8-2.6 log(10) reduction in colony count at 24 h. Vancomycin fAUC(24)/MIC of 85-170 (vancomycin MIC, 2-4 mg/L for VISA) resulted in a 0.4-0.7 log(10) reduction at 24 h. Vancomycin fAUC(24)/MIC of 5.3 (vancomycin MIC, 64 mg/L for VRSA) resulted in a limited effect. Conclusions Ceftobiprole T > MIC of > or =100% (Ceftobiprole MICs, or =3 log(10) killing) against MSSA, CA-MRSA, HA-MRSA, VISA and VRSA at 16 and 24 h. Vancomycin was bacteriostatic against MSSA, MRSA and VISA, while demonstrating no activity against VRSA.
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in vitro activity of Ceftobiprole against clinical isolates of pseudomonas aeruginosa obtained from canadian intensive care unit icu patients as part of the can icu study
Journal of Antimicrobial Chemotherapy, 2008Co-Authors: Andrew Walkty, Daryl J Hoban, James A Karlowsky, Melanie Decorby, Kim Nichol, George G ZhanelAbstract:Sir, In recent years, Pseudomonas aeruginosa isolates resistant to multiple classes of antimicrobial agents have become increasingly common. Several mechanisms may contribute to antimicrobial resistance among P. aeruginosa, including the production of a chromosomally encoded AmpC b-lactamase. Ceftobiprole (BAL9141), an investigational pyrrolidinone cephalosporin, is reported to have activity against a broad spectrum of clinically important Gram-negative bacteria including P. aeruginosa. Additionally, in vitro studies have demonstrated that Ceftobiprole is hydrolysed very slowly by AmpC cephalosporinases. The purpose of this report was to describe the in vitro activity of Ceftobiprole versus 419 clinical isolates of P. aeruginosa obtained from patients in an intensive care unit (ICU) setting. Cefepime was used as a comparator antimicrobial agent. From September 2005 to June 2006, inclusive, P. aeruginosa isolates were collected as part of the Canadian National Intensive Care Unit (CAN-ICU) Study. The CAN-ICU Study included 19 medical centres from all regions of Canada with active ICUs. Each centre submitted a maximum of 300 consecutive pathogens isolated from blood, urine, tissue/wound and respiratory specimens (one pathogen per cultured site per patient) of ICU patients. Centres were requested to only obtain ‘clinically important’ specimens from patients with a presumed infectious disease. Surveillance swabs, eye, ear, nose and throat swabs were excluded, as were anaerobic bacteria and fungi. Isolates were shipped to the reference laboratory (Health Sciences Centre, Winnipeg, MB, Canada) on Amies charcoal swabs, subcultured onto appropriate media and stocked in skimmed milk at 2808C until MIC testing was performed. The in vitro activities of Ceftobiprole and cefepime were determined by microbroth dilution in accordance with the CLSI guidelines. MIC interpretive standards for cefepime were defined according to CLSI breakpoints. At present, susceptibility breakpoints for Ceftobiprole do not exist. In total, 419 isolates of P. aeruginosa were collected as part of the CAN-ICU Study. The breakdown of these 419 isolates by specimen source was as follows: respiratory (69.0%), wound (12.4%), urine (10.7%) and blood (7.9%). The MIC distributions of Ceftobiprole and cefepime for the isolates were very similar (Table 1). At an antimicrobial concentration of 8 mg/L, 74.7% and 78.7% of our isolates would be inhibited by Ceftobiprole and cefepime, respectively. The MIC50 and MIC90 values of Ceftobiprole were 4 and 16 mg/L. The corresponding MIC50 and MIC90 values of cefepime were 4 and 32 mg/L. The MIC50/ MIC90 values of Ceftobiprole and cefepime were comparable, regardless of specimen source. Cross-resistance between Ceftobiprole and cefepime was observed. Of 43 cefepime-resistant isolates (MIC 32 mg/L), only 3 (7.0%) had an MIC of Ceftobiprole of 8 mg/L. Similarly, only 6 of 40 isolates (15%) with a Ceftobiprole MIC of 32 mg/L were susceptible to cefepime. In agreement with our results, previous studies have reported similar in vitro activity between Ceftobiprole and cefepime when evaluated against P. aeruginosa. A recent study by Pillar et al. documented a lower modal MIC of cefepime in comparison with Ceftobiprole against P. aeruginosa isolates (1 mg/L versus 2 mg/L). However, the MIC50 and MIC90 values were identical (4 and 16 mg/L respectively) for both antimicrobials. Our data demonstrate a high degree of cross-resistance between Ceftobiprole and cefepime. Hebeisen et al. have previously described the finding of cross-resistance between ceftazidime, cefepime and Ceftobiprole. These investigators reported the activity of Ceftobiprole against 17 ceftazidime-non-susceptible P. aeruginosa isolates (MIC50 of 16 mg/L and MIC90 of .64 mg/L for ceftazidime). The MIC50 and MIC90 values of Ceftobiprole against these isolates were 16 and .64 mg/L, respectively. The corresponding MIC50 and MIC90 values of cefepime versus the ceftazidime-non-susceptible isolates were 32 and 32 mg/L. Cross-resistance has also been described in a study by Pillar et al., where the MIC50/MIC90 values of Ceftobiprole against 491 ceftazidime-susceptible and 130 ceftazidime-non-susceptible P. aeruginosa isolates were 2/8 and 16/.32 mg/L, respectively. In summary, Ceftobiprole and cefepime demonstrated comparable in vitro activity against P. aeruginosa clinical isolates from Canadian ICUs and cross-resistance between these agents was common. Whether Ceftobiprole will be clinically useful in the treatment of serious infections caused by P. aeruginosa remains to be determined.