title: Pharmacokinetics and penetration of ceftazidime and avibactam into epithelial lining fluid in thigh- and lung-infected mice.
abstract: Ceftazidime and the β-lactamase inhibitor avibactam constitute a new, potentially highly active combination in the battle against extended-spectrum-β-lactamase (ESBL)-producing bacteria. To determine possible clinical use, it is important to know the pharmacokinetic profiles of the compounds related to each other in plasma and the different compartments of infection in experimentally infected animals and in humans. We used a neutropenic murine thigh infection model and lung infection model to study pharmacokinetics in plasma and epithelial lining fluid (ELF). Mice were infected with ca. 10(6) CFU of Pseudomonas aeruginosa intramuscularly into the thigh or intranasally to cause pneumonia and were given 8 different (single) subcutaneous doses of ceftazidime and avibactam in various combined concentrations, ranging from 1 to 128 mg/kg of body weight in 2-fold increases. Concomitant samples of serum and bronchoalveolar lavage fluid were taken at up to 12 time points until 6 h after administration. Pharmacokinetics of both compounds were linear and dose proportional in plasma and ELF and were independent of the infection type, with estimated half-lives (standard deviations [SD]) in plasma of ceftazidime of 0.28 (0.02) h and of avibactam of 0.24 (0.04) h and volumes of distribution of 0.80 (0.14) and 1.18 (0.34) liters/kg. The ELF-plasma (area under the concentration-time curve [AUC]) ratios (standard errors [SE]) were 0.24 (0.03) for total ceftazidime and 0.27 (0.03) for unbound ceftazidime; for avibactam, the ratios were 0.20 (0.02) and 0.22 (0.02), respectively. No pharmacokinetic interaction between ceftazidime and avibactam was observed. Ceftazidime and avibactam showed linear plasma pharmacokinetics that were independent of the dose combinations used or the infection site in mice. Assuming pharmacokinetic similarity in humans, this indicates that similar dose ratios of ceftazidime and avibactam could be used for different types and sites of infection.
authors: Department of Medical Microbiology and Infectious Diseases, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands.
authors: Johanna
authors: http://orcid.org/0000-0003-4387-4464
authors: J
authors: Berkhout
authors: Department of Medical Microbiology, Radboud University, Nijmegen Medical Center, Nijmegen, The Netherlands.
authors: Maria J
authors: MJ
authors: Melchers
authors: Department of Medical Microbiology and Infectious Diseases, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands.
authors: Anita C
authors: AC
authors: van Mil
authors: Department of Medical Microbiology, Radboud University, Nijmegen Medical Center, Nijmegen, The Netherlands Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors: Seyedmojtaba
authors: http://orcid.org/0000-0002-6194-7447
authors: S
authors: Seyedmousavi
authors: Department of Medical Microbiology, Radboud University, Nijmegen Medical Center, Nijmegen, The Netherlands.
authors: Claudia M
authors: CM
authors: Lagarde
authors: AstraZeneca Pharmaceuticals, Waltham, Massachusetts, USA.
authors: Wright W
authors: WW
authors: Nichols
authors: Department of Medical Microbiology, Radboud University, Nijmegen Medical Center, Nijmegen, The Netherlands Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, The Netherlands jwmouton@gmail.com.
authors: Johan W
authors: http://orcid.org/0000-0001-6736-4149
authors: JW
authors: Mouton
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics*; D053961:Azabicyclo Compounds / Q000493:pharmacokinetics*; D001992:Bronchoalveolar Lavage Fluid; D002442:Ceftazidime / Q000493:pharmacokinetics*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D004848:Epithelium / Q000378:metabolism*; D005260:Female; D006207:Half-Life; D008171:Lung Diseases / Q000382:microbiology; D051379:Mice; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000382:microbiology; D013848:Thigh / Q000382:microbiology; D065093:beta-Lactamase Inhibitors / Q000627:therapeutic use
chemical_list: D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D004791:Enzyme Inhibitors; D065093:beta-Lactamase Inhibitors; C543519:avibactam; D002442:Ceftazidime
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