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

Abstract

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...

Pharmacokinetic-Pharmacodynamic Analysis for Efficacy of Ceftaroline Fosamil in Patients with Acute Bacterial Skin and Skin Structure Infections

“…Findings for ceftaroline against S. aureus in a neutropenic-murine thigh infection model demonstrated that a median (min, max) f%TϾMIC of 26 (15,36) was associated with net bacterial stasis (10), an endpoint correlated with a high percentage of successful outcomes in patients with ABSSSI (2). Given the limited number of low f%TϾMIC values and the above-described uncertainty of the mathematical function in this region, it is difficult to evaluate the concordance of these data and precisely estimate the probability of microbiological response at a f%TϾMIC of 26.…”

“…The PK-PD index of interest in this evaluation was the percentage of time the free-drug concentration remained above the MIC (f%TϾMIC), the measure that has been demonstrated to be most predictive of ceftaroline efficacy on the basis of nonclinical data (10). The estimation of f%TϾMIC values was based on the MICs for baseline pathogens and a previously developed population PK model (11).…”

Pharmacokinetic/pharmacodynamic analysis to evaluate ceftaroline fosamil dosing regimens for the treatment of community-acquired bacterial pneumonia and complicated skin and skin-structure infections in patients with normal and impaired renal function

“…The best PK/PD index to predict the efficacy of ceftaroline is the percentage of the time for which the free serum concentration is above the MIC (fT >MIC ) [19]. The bacteriostatic effect of ceftaroline is achieved when unbound drug concentrations exceed the MIC for 30% of the dosing interval (fT >MIC > 30%) for Gram-negative bacilli.…”

Pharmacokinetic-Pharmacodynamic Target Attainment Analyses To EvaluateIn VitroSusceptibility Test Interpretive Criteria for Ceftaroline against Staphylococcus aureus and Streptococcus pneumoniae

“…For S. pneumoniae, f %TϾMIC targets associated with these endpoints were 35, 44, and 51, respectively. These studies evaluated four S. aureus isolates (including one MRSA isolate) and five S. pneumoniae isolates (one penicillin susceptible, one with intermediate sensitivity, and three penicillin resistant) (9). Nonclinical PK-PD targets associated with net bacterial stasis and 90% animal survival have been shown to be correlated with a high percentage of successful outcomes in patients with ABSSSI and pneumonia, respectively (17).…”

“…For each dosing regimen and renal function group, the percentage of simulated patients achieving PK-PD targets was assessed by MIC value. PK-PD targets were based on f %TϾMIC, the PK-PD index associated with efficacy for ceftaroline (9). Specific f %TϾMIC targets associated with various levels of bacterial reduction from baseline for S. aureus and S. pneumoniae based on data from a neutropenic murine thigh infection model were assessed.…”