dc.date.accessioned | 2021-10-04T23:00:58Z | |
dc.date.available | 2021-10-04T23:00:58Z | |
dc.date.created | 2021-10-04T23:00:58Z | |
dc.date.issued | 2021 | |
dc.identifier | https://hdl.handle.net/20.500.12866/9828 | |
dc.identifier | https://doi.org/10.1128/AAC.00692-21 | |
dc.description.abstract | Antibiotic combinations, including ceftazidime/avibactam (CAZ/AVI), are frequently employed to combat KPC-producing Klebsiella pneumoniae (KPC-Kp), though such combinations have not been rationally optimized. Clinical KPC-Kp isolates with common genes encoding aminoglycoside-modifying enzymes (AMEs), aac (69)-Ib9 or aac(69)-Ib, were used in static time-kill assays (n = 4 isolates) and the hollow- fiber infection model (HFIM; n = 2 isolates) to evaluate the activity of gentamicin, amikacin, and CAZ/AVI alone and in combinations. A short course, one-time aminoglycoside dose was also evaluated. Gentamicin plus CAZ/AVI was then tested in a mouse pneumonia model. Synergy with CAZ/AVI was more common with amikacin for aac(69)-Ib9-containing KPC-Kp but more common with gentamicin for aac(69)-Ibcontaining isolates in time-kill assays. In the HFIM, although the isolates were aminoglycoside- susceptible at baseline, aminoglycoside monotherapies displayed variable initial killing, followed by regrowth and resistance emergence. CAZ/AVI combined with amikacin or gentamicin resulted in undetectable counts 50 h sooner than CAZ/ AVI monotherapy against KPC-Kp with aac(69)-Ib9. CAZ/AVI monotherapy failed to eradicate KPC-Kp with aac(69)-Ib and a combination with gentamicin led to undetectable counts 70 h sooner than with amikacin. A one-time aminoglycoside dose with CAZ/AVI provided similar killing to aminoglycosides dosed for 7 days. In the mouse pneumonia model (n = 1 isolate), gentamicin and CAZ/AVI achieved a 6.0-log10CFU/ lung reduction at 24 h, which was significantly greater than either monotherapy (P<0.005). Aminoglycosides in combination with CAZ/AVI were promising for KPC-Kp infections; this was true even for a one-time aminoglycoside dose. Selecting aminoglycosides based on AME genes or susceptibilities can improve the pharmacodynamic activity of the combination | |
dc.language | eng | |
dc.publisher | American Society for Microbiology | |
dc.relation | Antimicrobial Agents and Chemotherapy | |
dc.relation | 1098-6596 | |
dc.rights | https://creativecommons.org/licenses/by-nc-nd/4.0/deed.es | |
dc.rights | info:eu-repo/semantics/restrictedAccess | |
dc.subject | Aminoglycoside-modifying enzymes | |
dc.subject | Aminoglycosides | |
dc.subject | Antimicrobial combinations | |
dc.subject | Carbapenemase | |
dc.subject | Klebsiella | |
dc.subject | KPC | |
dc.title | Generating genotype-specific aminoglycoside combinations with ceftazidime/Avibactam for KPC-Producing Klebsiella pneumoniae | |
dc.type | info:eu-repo/semantics/article | |