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Antibacterial Activity of Human Simulated Epithelial Lining Fluid Concentrations of Ceftazidime-Avibactam Alone or in Combination with Amikacin Inhale (BAY41-6551) against Carbapenem-Resistant Pseudomonas aeruginosa and Klebsiella pneumoniae.
Antimicrob Agents Chemother. 2018 07; 62(7)AA

Abstract

The role of inhalational combination therapy when treating carbapenem-resistant Pseudomonas aeruginosa and Klebsiella pneumoniae with newer beta-lactam/beta-lactamase inhibitors has not been established. Using a 72-h in vitro pharmacodynamic chemostat model, we simulated the human exposures achieved in epithelial lining fluid (ELF) following intravenous treatment with ceftazidime-avibactam (CZA) 2.5 g every 8 h (q8h) alone and in combination with inhaled amikacin (AMK-I) 400 mg q12h, a reformulated aminoglycoside designed for inhalational administration, against three P. aeruginosa isolates (CZA [ceftazidime/avibactam] MICs, 4/4 to 8/4 μg/ml; AMK-I MICs, 8 to 64 μg/ml) and three K. pneumoniae isolates (CZA MICs, 1/4 to 8/4 μg/ml; AMK-I MICs, 32 to 64 μg/ml). Combination therapy resulted in a significant reduction in 72-h CFU compared with that of CZA monotherapy against two of three P. aeruginosa isolates (-4.14 log10 CFU/ml, P = 0.027; -1.42 log10 CFU/ml, P = 0.020; and -0.4 log10 CFU/ml, P = 0.298) and two of three K. pneumoniae isolates (0.04 log10 CFU/ml, P = 0.963; -4.34 log10 CFU/ml, P < 0.001; and -2.34 log10 CFU/ml, P = 0.021). When measured by the area under the bacterial growth curve (AUBC) over 72 h, significant reductions were observed in favor of the combination regimen against all six isolates tested. AMK-I combination therapy successfully suppressed CZA resistance development in one K. pneumoniae isolate harboring blaKPC-3 that was observed during CZA monotherapy. These studies suggest a beneficial role for combination therapy with intravenous CZA and inhaled AMK when treating pneumonia caused by carbapenem-resistant Gram-negative bacteria.

Authors+Show Affiliations

Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA. Umm Al-Qura University, Makkah, Saudi Arabia.Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA.Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA david.nicolau@hhchealth.org. Division of Infectious Diseases, Hartford Hospital, Hartford, Connecticut, USA.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29914950

Citation

Almarzoky Abuhussain, Safa S., et al. "Antibacterial Activity of Human Simulated Epithelial Lining Fluid Concentrations of Ceftazidime-Avibactam Alone or in Combination With Amikacin Inhale (BAY41-6551) Against Carbapenem-Resistant Pseudomonas Aeruginosa and Klebsiella Pneumoniae." Antimicrobial Agents and Chemotherapy, vol. 62, no. 7, 2018.
Almarzoky Abuhussain SS, Kuti JL, Nicolau DP. Antibacterial Activity of Human Simulated Epithelial Lining Fluid Concentrations of Ceftazidime-Avibactam Alone or in Combination with Amikacin Inhale (BAY41-6551) against Carbapenem-Resistant Pseudomonas aeruginosa and Klebsiella pneumoniae. Antimicrob Agents Chemother. 2018;62(7).
Almarzoky Abuhussain, S. S., Kuti, J. L., & Nicolau, D. P. (2018). Antibacterial Activity of Human Simulated Epithelial Lining Fluid Concentrations of Ceftazidime-Avibactam Alone or in Combination with Amikacin Inhale (BAY41-6551) against Carbapenem-Resistant Pseudomonas aeruginosa and Klebsiella pneumoniae. Antimicrobial Agents and Chemotherapy, 62(7). https://doi.org/10.1128/AAC.00113-18
Almarzoky Abuhussain SS, Kuti JL, Nicolau DP. Antibacterial Activity of Human Simulated Epithelial Lining Fluid Concentrations of Ceftazidime-Avibactam Alone or in Combination With Amikacin Inhale (BAY41-6551) Against Carbapenem-Resistant Pseudomonas Aeruginosa and Klebsiella Pneumoniae. Antimicrob Agents Chemother. 2018;62(7) PubMed PMID: 29914950.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Antibacterial Activity of Human Simulated Epithelial Lining Fluid Concentrations of Ceftazidime-Avibactam Alone or in Combination with Amikacin Inhale (BAY41-6551) against Carbapenem-Resistant Pseudomonas aeruginosa and Klebsiella pneumoniae. AU - Almarzoky Abuhussain,Safa S, AU - Kuti,Joseph L, AU - Nicolau,David P, Y1 - 2018/06/26/ PY - 2018/01/18/received PY - 2018/04/03/accepted PY - 2018/6/20/pubmed PY - 2019/9/17/medline PY - 2018/6/20/entrez KW - aminoglycoside KW - cephalosporin KW - pharmacodynamics JF - Antimicrobial agents and chemotherapy JO - Antimicrob Agents Chemother VL - 62 IS - 7 N2 - The role of inhalational combination therapy when treating carbapenem-resistant Pseudomonas aeruginosa and Klebsiella pneumoniae with newer beta-lactam/beta-lactamase inhibitors has not been established. Using a 72-h in vitro pharmacodynamic chemostat model, we simulated the human exposures achieved in epithelial lining fluid (ELF) following intravenous treatment with ceftazidime-avibactam (CZA) 2.5 g every 8 h (q8h) alone and in combination with inhaled amikacin (AMK-I) 400 mg q12h, a reformulated aminoglycoside designed for inhalational administration, against three P. aeruginosa isolates (CZA [ceftazidime/avibactam] MICs, 4/4 to 8/4 μg/ml; AMK-I MICs, 8 to 64 μg/ml) and three K. pneumoniae isolates (CZA MICs, 1/4 to 8/4 μg/ml; AMK-I MICs, 32 to 64 μg/ml). Combination therapy resulted in a significant reduction in 72-h CFU compared with that of CZA monotherapy against two of three P. aeruginosa isolates (-4.14 log10 CFU/ml, P = 0.027; -1.42 log10 CFU/ml, P = 0.020; and -0.4 log10 CFU/ml, P = 0.298) and two of three K. pneumoniae isolates (0.04 log10 CFU/ml, P = 0.963; -4.34 log10 CFU/ml, P < 0.001; and -2.34 log10 CFU/ml, P = 0.021). When measured by the area under the bacterial growth curve (AUBC) over 72 h, significant reductions were observed in favor of the combination regimen against all six isolates tested. AMK-I combination therapy successfully suppressed CZA resistance development in one K. pneumoniae isolate harboring blaKPC-3 that was observed during CZA monotherapy. These studies suggest a beneficial role for combination therapy with intravenous CZA and inhaled AMK when treating pneumonia caused by carbapenem-resistant Gram-negative bacteria. SN - 1098-6596 UR - https://www.unboundmedicine.com/medline/citation/29914950/Antibacterial_Activity_of_Human_Simulated_Epithelial_Lining_Fluid_Concentrations_of_Ceftazidime_Avibactam_Alone_or_in_Combination_with_Amikacin_Inhale__BAY41_6551__against_Carbapenem_Resistant_Pseudomonas_aeruginosa_and_Klebsiella_pneumoniae_ L2 - http://aac.asm.org/cgi/pmidlookup?view=long&amp;pmid=29914950 DB - PRIME DP - Unbound Medicine ER -