dc.date.accessioned2021-10-04T23:00:58Z
dc.date.available2021-10-04T23:00:58Z
dc.date.created2021-10-04T23:00:58Z
dc.date.issued2021
dc.identifierhttps://hdl.handle.net/20.500.12866/9828
dc.identifierhttps://doi.org/10.1128/AAC.00692-21
dc.description.abstractAntibiotic 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.languageeng
dc.publisherAmerican Society for Microbiology
dc.relationAntimicrobial Agents and Chemotherapy
dc.relation1098-6596
dc.rightshttps://creativecommons.org/licenses/by-nc-nd/4.0/deed.es
dc.rightsinfo:eu-repo/semantics/restrictedAccess
dc.subjectAminoglycoside-modifying enzymes
dc.subjectAminoglycosides
dc.subjectAntimicrobial combinations
dc.subjectCarbapenemase
dc.subjectKlebsiella
dc.subjectKPC
dc.titleGenerating genotype-specific aminoglycoside combinations with ceftazidime/Avibactam for KPC-Producing Klebsiella pneumoniae
dc.typeinfo:eu-repo/semantics/article


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