In Vitro Pharmacokinetic and Pharmacodynamic Evaluation of S-013420 against Haemophilus influenzae and Streptococcus pneumoniae

Abstract

The pharmacokinetic (PK)/pharmacodynamic (PD) parameters and the antibacterial activity of S-013420, a novel bicyclolide, against Haemophilus influenzae and Streptococcus pneumoniae, including macrolide-resistant isolates, were investigated using an in vitro PD model. Various time-concentration curves were artificially constructed by modifying the PK data obtained in phase I studies. The activity against H. influenzae was evaluated using two parameters, that is, the area above the killing curve (AAC) and the viable cell reduction at 24 h. The relationships between the antibacterial activity of S-013420 and the three PK/PD parameters were investigated by fitting the data to the sigmoid maximum effective concentration model In antimicrobial chemotherapy, the pharmacokinetic (PK)/ pharmacodynamic (PD) concept has recently been used during drug development to determine susceptibility breakpoints, predict clinical efficacy, and optimize the antimicrobial regimen (1, 4, 13). Generally, antimicrobials can be categorized according to the dominant parameter of three PK/PD parameters correlated with antibacterial activity. These three parameters (1) are the area under the concentration-time curve from 0 to 24 h (AUC 0-24 )/MIC, the peak concentration (C max )/MIC, and the cumulative percentage of a 24-h period that the drug concentration exceeds the MIC under steady-state PK conditions (%T MIC ). Nonclinical PK/PD characterizations of antimicrobials using in vitro PD models or in vivo infection models have been reported (2,5,26,29). In general, AUC 0-24 /MIC is the dominant PK/PD parameter for macrolides, ketolides, and quinolones, while C max /MIC is the main parameter for quinolones and aminoglycosides and %T MIC is that for ␤-lactams (1, 4). Overall, nonclinical PK/PD data have agreed well with data obtained for infected patients, and a PK/PD evaluation would be helpful for cutting costs, addressing ethical issues, and shortening the duration of clinical trials (1, 4).Community-acquired respiratory tract infections (RTIs), such as community-acquired pneumonia, acute exacerbations of chronic bronchitis, sinusitis, and acute otitis media, are among the most common infectious diseases for which oral antibiotics are prescribed in primary clinical settings and are mainly caused by Streptococcus pneumoniae and Haemophilus influenzae (6). The macrolide antimicrobials, including clarithromycin and azithromycin, are often used for the treatment of community-acquired RTIs. However, the decreased susceptibility of S. pneumoniae to macrolide agents is a key problem worldwide. Recent reports have suggested that pneumococcal macrolide resistance rates were about 35% in some regions (7,14,23). In S. pneumoniae, two main mechanisms of macrolide resistance were reported, i.e., active efflux due to mef genes and ribosomal modification mediated by erm genes (11). S-013420 (EDP-420, EP-013420) is a novel bicyclolide (bridged bicyclic macrolide) that is characterized by a 6,11-O-bridged structure discovered by Enanta Pharmaceuticals, Inc. ...

Pharmacokinetic/Pharmacodynamic Modeling for Concentration-Dependent Bactericidal Activity of a Bicyclolide, Modithromycin

“…As the details of these experiments are given in the Refs . and , only general information for both experiments is described here.…”

“…In the above time‐kill experiments, cation‐adjusted Mueller Hinton broth (CAMHB) was used for S. aureus SR20405, Haemophilus test medium (HTM) was for H. influenzae strains and CAMHB supplemented with 5% lysed horse blood (CAMHB‐LHB) was for S. pneumoniae SR26132. The number of viable bacterial cells was determined by counting the number of colonies on agar plates using brain heart infusion agar (BHIA), BHIA with 2.5% enrichment and BHIA with 5% defibrinated horse blood (DHB) for S. aureus , H. influenzae , and S. pneumoniae , respectively.…”

“…The lower limit of quantification was 100 CFU/mL in both experiments. The MIC values were determined by a broth microdilution method using CAMHB, HTM, and CAMHB‐LHB for S. aureus SR20405, H. influenzae strains, and S. pneumoniae SR26132, respectively …”

“…The serial numbers (Comb. #) were assigned to the drug-bacterium combinations as defined in Table 1 In the dynamic experiments, 22 "autosimulation Shionogi dilution-type equipment" was used to evaluate the bactericidal activity of modithromycin by mechanically simulating in vivo drug concentration-time courses. The concentration-time courses were simulated by addition of the drug solution to the bacterial suspension or dilution of the bacterial suspension with adding the medium.…”

Macrolides and Ketolides

“…Cethromycin was shown to be bactericidal, even against macrolide-resistant strains (Neuhauser et al 2003 ). Modithromycin activity is AUC/MIC dependent, as the other ketolides, with simulated values of approximatey 10 and 16-20 h required to reach a maximal effect against H. infl uenzae and S. pneumoniae, respectively (Homma et al 2010 ) . The latter value is thus of the same order of magnitude as what has been reported for telithromycin.…”