title: Pharmacodynamics of S-3578, a novel cephem, in murine lung and systemic infection models.
abstract: S-3578 is a novel beta-lactam with enhanced activity against drug-resistant gram-positive cocci such as methicillin-resistant Staphylococcus aureus (MRSA). We used murine penicillin-resistant Streptococcus pneumoniae lung infection and neutropenic murine systemic MRSA infection models to determine the pharmacokinetic (PK)-pharmacodynamic (PD) parameter that best correlated with efficacy. Pharmacokinetic studies revealed that the maximum concentration in serum/dose values for S-3578 and cefepime in plasma in the lung infection model were 1.21 to 1.54 and 0.97 to 1.29, respectively; those for S-3578 in plasma in the systemic infection model were 0.78 to 1.02. The area under the concentration-time curve (AUC)/dose values for S-3578 and cefepime in plasma in the lung infection model were 0.98 to 1.13 and 0.77 to 1.04, respectively, and those for S-3578 in plasma in the systemic infection model were 1.03 to 1.11. The half-lives of S-3578 and cefepime in plasma in the lung infection model were 0.29 to 0.38 and 0.29 to 0.34, respectively, and those of S-3578 in plasma in the systemic infection model were 0.40 to 0.61. The time above the MIC was the PK-PD parameter that best correlated with efficacy in the murine lung infection model (R(2) = 84 and 92% for S-3578 and cefepime in plasma, respectively). There was a twofold increase in the dose of S-3578 in the systemic infection model compared to that in the pneumonia model, yet the AUCs were the same. This may be due to the different MICs for the two pathogens.
authors.affiliation: Department of Microbiology, Toho University School of Medicine, Omori-nishi, 5-21-16, Ota-ku, Tokyo 143-8540, Japan. shuichi@med.toho-u.ac.jp
authors.forename: Shuichi
authors.initials: S
authors.lastname: Miyazaki
authors.forename: Kenichi
authors.initials: K
authors.lastname: Okazaki
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Tsuji
authors.forename: Keizo
authors.initials: K
authors.lastname: Yamaguchi
mesh_terms: D000818:Animals; D019540:Area Under Curve; D000077723:Cefepime; D002511:Cephalosporins / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D015169:Colony Count, Microbial; D005260:Female; D007279:Injections, Subcutaneous; D008168:Lung / Q000378:metabolism*; D016106:Methicillin Resistance; D051379:Mice; D008808:Mice, Inbred CBA; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D011018:Pneumonia, Pneumococcal / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D018805:Sepsis / Q000188:drug therapy / Q000378:metabolism / Q000382:microbiology; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects; D016019:Survival Analysis; D014018:Tissue Distribution
chemical_list: C471249:7-(2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido)-3-(1-(3-methylaminopropyl)-1H-imidazo(4,5-b)pyridinium-4-yl)methyl-3-cephem-4-carboxylate; D002511:Cephalosporins; D000077723:Cefepime