Can Ceftazidime-Avibactam and Aztreonam Overcome β-Lactam Resistance Conferred by Metallo-β-Lactamases in Enterobacteriaceae?
Based upon knowledge of the hydrolytic profile of major β-lactamases found in Gram-negative bacteria, we tested the efficacy of the combination of ceftazidime-avibactam (CAZ-AVI) with aztreonam (ATM) against carbapenem-resistant enteric bacteria possessing metallo-β-lactamases (MBLs). Disk diffusion and agar-based antimicrobial susceptibility testing were initially performed to determine thein vitroefficacy of a unique combination of CAZ-AVI and ATM against 21 representativeEnterobacteriaceaeisolates with a complex molecular background that includedblaIMP,blaNDM,blaOXA-48,blaCTX-M,blaAmpC, and combinations thereof. Time-kill assays were conducted, and thein vivoefficacy of this combination was assessed in a murine neutropenic thigh infection model. By disk diffusion assay, all 21 isolates were resistant to CAZ-AVI alone, and 19/21 were resistant to ATM. Thein vitroactivity of CAZ-AVI in combination with ATM against diverseEnterobacteriaceaepossessing MBLs was demonstrated in 17/21 isolates, where the zone of inhibition was ≥21 mm. All isolates demonstrated a reduction in CAZ-AVI agar dilution MICs with the addition of ATM. At 2 h, time-kill assays demonstrated a ≥4-log10-CFU decrease for all groups that had CAZ-AVI with ATM (8 μg/ml) added, compared to the group treated with CAZ-AVI alone. In the murine neutropenic thigh infection model, an almost 4-log10-CFU reduction was noted at 24 h for CAZ-AVI (32 mg/kg every 8 h [q8h]) plus ATM (32 mg/kg q8h) versus CAZ-AVI (32 mg/kg q8h) alone. The data presented herein require us to carefully consider this new therapeutic combination to treat infections caused by MBL-producingEnterobacteriaceae.
Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.
Steven
S
Marshall
Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.|Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
Andrea M
AM
Hujer
Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.|Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.|Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
Laura J
LJ
Rojas
Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.
Krisztina M
KM
Papp-Wallace
Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, California, USA.
Romney M
RM
Humphries
Division of Infectious Diseases, Keck School of Medicine at USC and the Los Angeles County-USC Medical Center, Los Angeles, California, USA.
Brad
B
Spellberg
Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.|Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
Kristine M
KM
Hujer
Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.
Emma K
EK
Marshall
Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.|Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
Susan D
SD
Rudin
Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.|Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
Federico
F
Perez
Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.
Brigid M
BM
Wilson
Infectious Disease Doctors Medical Group, Walnut Creek, California, USA.
Ronald B
RB
Wasserman
John Muir Health, Walnut Creek, California, USA.
Linda
L
Chikowski
The University of Queensland, UQ Centre for Clinical Research, Brisbane, Queensland, Australia.
David L
DL
Paterson
Instituto de Biología Molecular y Celular de Rosario Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina, Universidad Nacional de Rosario, Rosario, Argentina.
Alejandro J
AJ
Vila
Division of Infectious Diseases, University of North Carolina, Chapel Hill, North Carolina, USA.
David
D
van Duin
Public Health Research Institute Center, New Jersey Medical School-Rutgers University, Newark, New Jersey, USA.
Barry N
BN
Kreiswirth
University of California, San Francisco, and San Francisco General Hospital, San Francisco, California, USA.
Henry F
HF
Chambers
Division of Infectious Diseases, Department of Medicine, and Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina, USA.
Vance G
VG
Fowler
Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
Michael R
MR
Jacobs
University of North Texas Health Science Center, Fort Worth, Texas, USA.
Mark E
ME
Pulse
University of North Texas Health Science Center, Fort Worth, Texas, USA.
William J
WJ
Weiss
Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA robert.bonomo@va.gov.|Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.|Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.|Departments of Pharmacology, Biochemistry, and Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
Robert A
RA
Bonomo
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D001398:Aztreonam / Q000494:pharmacology*; D002442:Ceftazidime / Q000494:pharmacology*; D015169:Colony Count, Microbial; D003520:Cyclophosphamide; D004334:Drug Administration Schedule; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D004755:Enterobacteriaceae / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D004756:Enterobacteriaceae Infections / Q000188:drug therapy* / Q000382:microbiology; D005260:Female; D015870:Gene Expression; D006801:Humans; D007710:Klebsiella Infections / Q000150:complications / Q000188:drug therapy / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D051379:Mice; D008826:Microbial Sensitivity Tests; D009503:Neutropenia / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy / Q000382:microbiology; D010957:Plasmids / Q000737:chemistry / Q000378:metabolism; D018461:Soft Tissue Infections / Q000150:complications / Q000188:drug therapy / Q000382:microbiology; D013848:Thigh; D018440:beta-Lactam Resistance / Q000187:drug effects / Q000235:genetics; D001618:beta-Lactamases / Q000235:genetics / Q000378:metabolism
D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D004338:Drug Combinations; C000595613:avibactam, ceftazidime drug combination; D003520:Cyclophosphamide; D002442:Ceftazidime; D001618:beta-Lactamases; D001398:Aztreonam
avibactam; aztreonam; ceftazidime; disk diffusion; metallo-β-lactamases