Plasma and Epithelial Lining Fluid Pharmacokinetics of Ceftolozane and Tazobactam Alone and in Combination in Mice
| Autor: | Claudia M. Lagarde, A.C. Van Mil, Seyedmojtaba Seyedmousavi, Maria J. Melchers, Eleftheria Mavridou, Johan W. Mouton |
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| Přispěvatelé: | Medical Microbiology & Infectious Diseases |
| Rok vydání: | 2015 |
| Předmět: |
Tazobactam
medicine.drug_class Klebsiella pneumoniae Cephalosporin Penicillanic Acid Pharmacology Mice Pharmacokinetics medicine Escherichia coli polycyclic compounds Animals Pharmacology (medical) medicine.diagnostic_test biology Chemistry Liter biochemical phenomena metabolism and nutrition biology.organism_classification bacterial infections and mycoses Anti-Bacterial Agents Cephalosporins Infectious Diseases Bronchoalveolar lavage lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4] Thigh Pharmacodynamics Ceftolozane Female medicine.drug Protein Binding |
| Zdroj: | Antimicrobial Agents and Chemotherapy, 59, 6, pp. 3373-6 Antimicrobial Agents and Chemotherapy, 59, 3373-6 Antimicrobial Agents & Chemotherapy, 59(6), 3373-3376. American Society for Microbiology |
| ISSN: | 0066-4804 |
| Popis: | Ceftolozane is a new cephalosporin with activity against Gram-negative and Gram-positive microorganisms. However, the compound is susceptible to degradation by extended-spectrum beta-lactamases (ESBLs). Tazobactam is an ESBL inhibitor and is combined with ceftolozane to broaden its activity. Surprisingly, although tazobactam has been available for over 20 years, few if any reliable data exist on the tazobactam pharmacokinetic (PK) properties in mice. To evaluate the PK and pharmacodynamic (PD) relationships in mice, the PK properties of tazobactam and ceftolozane were extensively investigated. Thigh-infected neutropenic CD-1 mice were injected intraperitoneally with a single 0.1-ml dose containing ceftolozane, tazobactam, or both compounds. Ceftolozane was applied in 2-fold-increasing doses of 4 mg/kg of body weight to 64 mg/kg alone or in combination. Tazobactam was combined in reverse doses (thus, 64/4 mg/kg, 32/8 mg/kg, etc.) ( n = 2 per time point). In separate validation experiments, ceftolozane-tazobactam was given alone or in combination at 32/8 mg/kg and 8/32 mg/kg ( n = 4 per time point). Plasma samples (one per mouse) and bronchoalveolar lavage samples were collected at up to 12 time points until 6 h after administration. There were no significant differences in the ceftolozane and tazobactam PK alone versus combined, indicating no PK interaction. The PKs were linear and dose proportional for both compounds and showed a good penetration in the epithelial lining fluid. The estimated mean (standard deviation) half-life of ceftolozane was 0.287 h (0.031 h), and that of tazobactam was 0.176 h (0.026), and the V was 0.43 liter/kg and 1.14 liter/kg, respectively. The estimates of tazobactam parameters can also be used to (re)interpret PD data. |
| Databáze: | OpenAIRE |
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