Use of Monte Carlo Simulations To Select Therapeutic Doses and Provisional Breakpoints of BAL9141

Mouton, Johan W.; Schmitt‐Hoffmann, Anne; Shapiro, Stuart; Nashed, Norman; Punt, Nieko

doi:10.1128/aac.48.5.1713-1718.2004

Cited by 70 publications

(63 citation statements)

References 25 publications

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“…Using percent TϾMICs as a continuous variable in a logistic regression model demonstrated that percent TϾMIC was a predictor of clinical cure and confirms a preclinical study of ceftobiprole (5) and earlier modeling studies (11,13).…”

Section: Discussionmentioning

confidence: 73%

“…Using time-concentration data from 12 volunteers in a multiple-ascending-dose study, Mouton et al (13) concluded that ceftobiprole at 750 mg every 12 h would have a high probability of therapeutic efficacy for gram-positive infections, including MRSA. Lodise et al (11) completed additional simulations of the PD profile of ceftobiprole at 500 mg every 8 h as a 2-h infusion.…”

Section: Discussionmentioning

confidence: 99%

“…Combining this PK-PD measure with PK modeling allows the effects of variations in pathogen susceptibility and differences between hosts on the efficacy of ceftobiprole to be investigated. Mouton et al (13) and Lodise et al (11) used time-concentration data in Monte Carlo simulations to assess the probability of ceftobiprole succeeding as therapy. As these two analyses included the pharmacokinetics of ceftobiprole as defined in phase I studies and in a phase II study with subjects with cSSSI, they are estimates of what a dosing regimen might accomplish.…”

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confidence: 99%

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Pharmacodynamic Profiling of Ceftobiprole for Treatment of Complicated Skin and Skin Structure Infections

Kimko

Nandy

et al. 2009

Antimicrob Agents Chemother

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Ceftobiprole, a broad-spectrum cephalosporin with activity against methicillin (meticillin)-resistant staphylococci, was statistically noninferior to a combination of vancomycin plus ceftazidime in patients with complicated skin and skin structure infections (cSSSI). This analysis used data from this clinical trial to determine the relationship between therapeutic outcome and the percentage of time that the unbound ceftobiprole concentration exceeds the MIC (percent T>MIC). From the trial of ceftobiprole (500 mg every 8 h, 2-h infusion) for cSSSI due to gram-positive and/or gram-negative bacteria, data from 309 patients in the microbiological intent-to-treat analysis set with measured ceftobiprole concentrations and baseline MICs were used to assess the relationship between percent T>MIC and therapeutic outcome. Individual pharmacokinetic (PK) profiles were obtained from a three-compartment population PK model. The relationship between percent T>MIC and a clinical cure was determined. For the clinical trial dosing regimen, individual percent T>MICs were used to calculate fractional target attainment rates (TARs) for >30 and >50% T>MIC targets at various MICs. There was a statistically significant relationship between achieving a >30 or >50% T>MIC and a clinical cure (P ‫؍‬ 0.003 and P ‫؍‬ 0.007, respectively; Pearson's 2 test). The fractional TAR was greater than 90% at a MIC of <4 mg/liter for patients with normal renal function. A relationship between percent T>MIC and a clinical cure with ceftobiprole was demonstrated. A ceftobiprole regimen of 500 mg every 8 h as a 2-h infusion has a high probability of achieving a target of >30 or >50% T>MIC for patients with cSSSI due to gram-positive and gram-negative pathogens.

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Pharmacodynamic Profiling of Ceftobiprole for Treatment of Complicated Skin and Skin Structure Infections

Kimko

Nandy

et al. 2009

Antimicrob Agents Chemother

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“…A variety of in vitro and in vivo studies have demonstrated that the killing activity of beta-lactam antibiotics is not enhanced by exposure to drug concentrations far exceeding the MIC (1,4,11,13,14,17,18). Furthermore, PAE studies have demonstrated minimal persistent effects with drugs from the beta-lactam class with most bacteria.…”

Section: Discussionmentioning

confidence: 99%

Pharmacodynamics of a New Cephalosporin, PPI-0903 (TAK-599), Active against Methicillin-Resistant Staphylococcus aureus in Murine Thigh and Lung Infection Models: Identification of an In Vivo Pharmacokinetic-Pharmacodynamic Target

Andes

Craig

2006

Antimicrob Agents Chemother

131

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PPI-0903 is a new cephalosporin with broad-spectrum activity, including beta-lactam-resistant Streptococcus pneumoniae and Staphylococcus aureus. We used the neutropenic murine thigh and lung infection models to examine the pharmacodynamic characteristics of PPI-0903. Serum drug levels following four fourfold-escalating single doses of PPI-0903 were measured by microbiologic assay. In vivo postantibiotic effects (PAEs) were determined after doses of 1.56, 6.25, 25, and 100 mg/kg of body weight in mice infected with S. pneumoniae ATCC 10813, S. aureus ATCC 29213, or Escherichia coli ATCC 25922. Dose fractionation studies over a 24-h dose range of 0.39 to 1,600 mg/kg were administered every 3, 6, 12, or 24 hours. Nonlinear regression analysis was used to determine which pharmacokinetic-pharmacodynamic (PK-PD) index (total and free 65% drug) best correlated with CFU/thigh at 24 h. Similar to other beta-lactam antibiotics, PPI-0903 produced short to modest in vivo PAEs with either S. pneumoniae or E. coli. The percent time that serum concentrations were above the MIC (%T>MIC) was the PK-PD index that best correlated with efficacy (R 2 ‫؍‬ 84 to 88% for the three organisms, compared with 9 to 41% for peak/MIC and 30 to 82% for the area under the concentration-time curve/MIC). In subsequent studies we used the neutropenic murine thigh infection model to determine if the magnitude of the free-drug %T>MIC needed for efficacy of PPI-0903 varied among pathogens (including resistant strains). Mice infected with one of five isolates of S. pneumoniae, four isolates of S. aureus, or four gram-negative bacilli were treated for 24 h with 0.10 to 400 mg/kg of PPI-0903 every 6 h. A sigmoid dose-response model was used to estimate the doses (mg/kg/24 h) required to achieve a net bacteriostatic affect over 24 h and to produce a reduction in the burden of organisms from the start of therapy by 1 and 2 log 10 CFU/thigh. MICs ranged from 0.008 to 1 g/ml. Mean free-drug %T>MICs ؎ the standard deviation associated with the static effect endpoint for S. pneumoniae, S. aureus, and gram-negative isolates were 39 ؎ 9, 26 ؎ 8, and 32 ؎ 6, respectively. Methicillin and penicillin resistance did not alter the magnitude of free-drug %T>MIC required for efficacy. The free-drug %T>MIC necessary for efficacy was slightly reduced in animals with normal neutrophil counts. Treatment effect was similar in both the thigh and lung infection models. The pharmacodynamic characteristics of PPI-0903 are similar to those of other compounds within the cephalosporin class.PPI-0903 is a new cephalosporin with broad-spectrum antimicrobial activity and is in early clinical development. PPI-0903 has enhanced potency against gram-positive cocci, including multiply drug-resistant Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus (10).The goals of our experiments were to characterize the in vivo time course antimicrobial activity of PPI-0903 and determine the pharmacokinetic-pharmacodynamic (PK-PD) index and index magnitude predictive of effica...

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“…6 This profile contributes to the broad-spectrum antibacterial activity against gram-negative and grampositive bacteria of this cephalosporin. No breakpoints have been established for ceftobiprole, but based on minimum inhibitory concentration (MIC) distribution and pharmacokinetic/pharmacodynamic information, Mouton et al 7 proposed a provisional breakpoint of 4 µg/mL for susceptible Gram-positive microorganisms. This breakpoint may not be applicable to Gram-negative bacteria.…”

Section: In Vitro Antibacterial Activity: Ceftobiprole and The Penicimentioning

confidence: 99%

Emerging agents to combat complicated and resistant infections: focus on ceftobiprole

Bustos

Pozo²

2010

IDR

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Antimicrobial resistance is a global concern. Over the past few years, considerable efforts and resources have been expended to detect, monitor, and understand at the basic level the many different facets of emerging and increasing resistance. Development of new antimicrobial agents has been matched by the development of new mechanisms of resistance by bacteria. Current antibiotics act at a variety of sites within the target bacteria, including the cross-linking enzymes in the cell wall, various ribosomal enzymes, nucleic acid polymerases, and folate synthesis. Ceftobiprole is a novel parenteral cephalosporin with high affinity for most penicillin-binding proteins, including the mecA product penicillin-binding protein 2a, rendering it active against methicillin-resistant staphylococci. Its in vitro activity against staphylococci and multiresistant pneumococci, combined with its Gram-negative spectrum comparable to that of other extended-spectrum cephalosporins, its stability against a wide range of beta-lactamases, and its pharmacokinetic and safety profiles make ceftobiprole an attractive and well tolerated new antimicrobial agent. The US Food and Drug Administration granted ceftobiprole medocaril fast-track status in 2003 for the treatment of complicated skin infections and skin structure infections due to methicillin-resistant staphylococci, and subsequently extended this to treatment of hospital-acquired pneumonia, including ventilator-associated pneumonia due to suspected or proven methicillin-resistant Staphylococcus aureus.

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Use of Monte Carlo Simulations To Select Therapeutic Doses and Provisional Breakpoints of BAL9141

Cited by 70 publications

References 25 publications

Pharmacodynamic Profiling of Ceftobiprole for Treatment of Complicated Skin and Skin Structure Infections

Pharmacodynamic Profiling of Ceftobiprole for Treatment of Complicated Skin and Skin Structure Infections

Pharmacodynamics of a New Cephalosporin, PPI-0903 (TAK-599), Active against Methicillin-Resistant Staphylococcus aureus in Murine Thigh and Lung Infection Models: Identification of an In Vivo Pharmacokinetic-Pharmacodynamic Target

Emerging agents to combat complicated and resistant infections: focus on ceftobiprole

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