ABSTRACT
Due to the substantial interspecies differences in drug metabolism and disposition, drug-induced liver injury (DILI) in humans is often not predicted by studies performed in animal species. For example, a drug (bosentan) used to treat pulmonary artery hypertension caused unexpected cholestatic liver toxicity in humans, which was not predicted by preclinical toxicology studies in multiple animal species. In this study, we demonstrate that NOG mice expressing a thymidine kinase transgene (TK-NOG) with humanized livers have a humanized profile of biliary excretion of a test (cefmetazole) drug, which was shown by an in situ perfusion study to result from interspecies differences in the rate of biliary transport and in liver retention of this drug. We also found that readily detectable cholestatic liver injury develops in TK-NOG mice with humanized livers after 1 week of treatment with bosentan (160, 32, or 6 mg/kg per day by mouth), whereas liver toxicity did not develop in control mice after 1 month of treatment. The laboratory and histologic features of bosentan-induced liver toxicity in humanized mice mirrored that of human subjects. Because DILI has become a significant public health problem, drug safety could be improved if preclinical toxicology studies were performed using humanized TK-NOG.
Subject(s)
Cefmetazole/pharmacokinetics , Chemical and Drug Induced Liver Injury/metabolism , Cholestasis/metabolism , Disease Models, Animal , Mice, Transgenic , Thymidine Kinase/genetics , Animals , Bosentan , Chemical and Drug Induced Liver Injury/complications , Chemical and Drug Induced Liver Injury/pathology , Cholestasis/etiology , Cholestasis/pathology , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Ganciclovir/administration & dosage , Ganciclovir/pharmacology , Hepatocytes/metabolism , Hepatocytes/physiology , Hepatocytes/transplantation , Humans , Metabolic Clearance Rate , Species Specificity , Sulfonamides/administration & dosage , Sulfonamides/pharmacology , Sulfonamides/toxicity , Thymidine Kinase/metabolism , Tissue Distribution , TransgenesABSTRACT
Intra-abdominal abscess is seldom adequately treated by systemic antibiotics alone and often requires surgical or computed tomography-guided drainage for resolution. Abscess penetration of six currently used antibiotics was examined in a murine intra-abdominal abscess model. Ampicillin/sulbactam, cefmetazole, clindamycin, and trospectomycin penetrated intra-abdominal abscesses to a greater degree than cefoxitin and ceftriaxone. Abscess pus antibiotic levels were not significantly higher after multiple doses than after a single dose. Pus antibiotic levels below the MIC90 for Bacteroides and E. coli within intra-abdominal abscess were observed for most antibiotics with the doses used in this study. Selection of antibiotics with a greater ability to penetrate abscess may be important in optimally treating patients with abdominal infection.
Subject(s)
Abdominal Abscess/drug therapy , Anti-Bacterial Agents/pharmacokinetics , Abdominal Abscess/blood , Ampicillin/pharmacokinetics , Ampicillin/therapeutic use , Animals , Anti-Bacterial Agents/blood , Anti-Bacterial Agents/therapeutic use , Bacteroides Infections/blood , Bacteroides Infections/drug therapy , Bacteroides fragilis , Cefmetazole/pharmacokinetics , Cefmetazole/therapeutic use , Cefoxitin/pharmacokinetics , Cefoxitin/therapeutic use , Ceftriaxone/pharmacokinetics , Ceftriaxone/therapeutic use , Clindamycin/pharmacokinetics , Clindamycin/therapeutic use , Drug Evaluation, Preclinical , Drug Therapy, Combination/pharmacokinetics , Drug Therapy, Combination/therapeutic use , Escherichia coli Infections/blood , Escherichia coli Infections/drug therapy , Hydrogen-Ion Concentration , Male , Mice , Microbial Sensitivity Tests , Spectinomycin/analogs & derivatives , Spectinomycin/pharmacokinetics , Spectinomycin/therapeutic use , Sulbactam/pharmacokinetics , Sulbactam/therapeutic useABSTRACT
The review is concerned with the description of the antibiotics belonging to cephamycins. The data on the chemical structure of cefmetazole and other cephamycins and the mechanisms of their action are presented. The peculiarities of the binding to penicillin-binding proteins and the stability to the action of various beta-lactamases are discussed. The spectrum of the antibacterial activity of cefmetazole against gram-positive and gram-negative aerobes and anaerobes, as well as the antibiotic pharmacokinetics is described. The literature data on the clinical efficacy of cefmetazole in the treatment of infectious diseases of various etiology and localization and the data on the drug tolerance and the incidence of adverse reactions are summarized. The indications to the use of cefmetazole and other cephamycins are substantiated.