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Generating genotype-specific aminoglycoside combinations with ceftazidime/Avibactam for KPC-Producing Klebsiella pneumoniae

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dc.contributor.author Huang, Yangin
dc.contributor.author Sokolowski, Karol
dc.contributor.author Rana, Amisha
dc.contributor.author Singh, Nidhi
dc.contributor.author Wang, Jiping
dc.contributor.author Chen, Ke
dc.contributor.author Lang, Yinzhi
dc.contributor.author Zhou, Jieqiang
dc.contributor.author Kadiyala, Neera
dc.contributor.author Krapp, Fiorella
dc.contributor.author Ozer, Egon A.
dc.contributor.author Hauser, Alan R.
dc.contributor.author Li, Jian
dc.contributor.author Bulitta, Jürgen B.
dc.contributor.author Bulman, Zackery P.
dc.date.accessioned 2021-10-04T23:00:58Z
dc.date.available 2021-10-04T23:00:58Z
dc.date.issued 2021
dc.identifier.uri https://hdl.handle.net/20.500.12866/9828
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 en_US
dc.language.iso eng
dc.publisher American Society for Microbiology
dc.relation.ispartofseries Antimicrobial Agents and Chemotherapy
dc.rights info:eu-repo/semantics/restrictedAccess
dc.rights.uri https://creativecommons.org/licenses/by-nc-nd/4.0/deed.es
dc.subject Aminoglycoside-modifying enzymes en_US
dc.subject Aminoglycosides en_US
dc.subject Antimicrobial combinations en_US
dc.subject Carbapenemase en_US
dc.subject Klebsiella en_US
dc.subject KPC en_US
dc.title Generating genotype-specific aminoglycoside combinations with ceftazidime/Avibactam for KPC-Producing Klebsiella pneumoniae en_US
dc.type info:eu-repo/semantics/article
dc.identifier.doi https://doi.org/10.1128/AAC.00692-21
dc.subject.ocde https://purl.org/pe-repo/ocde/ford#3.02.21
dc.relation.issn 1098-6596


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