title: Microbiological interaction studies between ceftazidime-avibactam and pulmonary surfactant and between ceftazidime-avibactam and antibacterial agents of other classes.
abstract: For an antibacterial agent to be considered for clinical studies in nosocomial pneumonia (NP), it should be active in the presence of pulmonary surfactant. Furthermore, owing to the common practice of treating such infections with more than one antibacterial agent, it should be free of antagonistic interactions with agents of other classes. The aim of this study was to demonstrate the effect of pulmonary surfactant on the activity of ceftazidime and ceftazidime-avibactam and to determine the interaction (if any) of ceftazidime-avibactam and six antimicrobial agents common in the treatment of NP. Minimum inhibitory concentration (MIC) determination for ceftazidime and ceftazidime-avibactam was performed with and without the presence of four concentrations of bovine pulmonary surfactant, and a chequerboard assay was used to determine any interaction between ceftazidime and ceftazidime-avibactam with tobramycin, levofloxacin, linezolid, vancomycin, tigecycline and colistin. Here we report that the in vitro antimicrobial activity of ceftazidime-avibactam against β-lactamase-producing Gram-negative bacteria remained unaltered in the presence of pulmonary surfactant at concentrations that antagonised the antimicrobial activity of daptomycin. Furthermore, in chequerboard interaction studies, an absence of antagonism was demonstrated between ceftazidime-avibactam and six antimicrobial agents of different classes when tested against aerobic species frequently isolated from NP. The results support the further investigation of ceftazidime-avibactam as a potential treatment for NP caused by susceptible bacteria.
authors.affiliation: LGC Group, Fordham, UK. Electronic address: john.dallow@gmail.com.
authors.forename: John
authors.initials: J
authors.lastname: Dallow
authors.affiliation: AstraZeneca Pharmaceuticals LP, Waltham, MA, USA.
authors.forename: Linda G
authors.initials: LG
authors.lastname: Otterson
authors.affiliation: AstraZeneca Pharmaceuticals LP, Waltham, MA, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Huband
authors.affiliation: Cerexa, Inc. (a subsidiary of Forest Laboratories, Inc.), Oakland, CA, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Krause
authors.affiliation: AstraZeneca Pharmaceuticals LP, Waltham, MA, USA.
authors.forename: Wright W
authors.initials: WW
authors.lastname: Nichols
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D053961:Azabicyclo Compounds / Q000494:pharmacology; D002442:Ceftazidime / Q000494:pharmacology; D003428:Cross Infection; D004359:Drug Therapy, Combination; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000201:enzymology; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy* / Q000382:microbiology; D006801:Humans; D008826:Microbial Sensitivity Tests; D008911:Minocycline / Q000031:analogs & derivatives / Q000494:pharmacology; D018410:Pneumonia, Bacterial / Q000188:drug therapy* / Q000382:microbiology; D011663:Pulmonary Surfactants / Q000494:pharmacology*; D000078304:Tigecycline; D014031:Tobramycin / Q000494:pharmacology; D001618:beta-Lactamases / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D011663:Pulmonary Surfactants; D000078304:Tigecycline; C543519:avibactam; D002442:Ceftazidime; D001618:beta-Lactamases; D008911:Minocycline; D014031:Tobramycin
keywords: Combined therapy; Gram-negative infections; Pneumonia; β-Lactam; β-Lactamase