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

Yanqin Huang; Karol Sokolowski; Amisha Rana; Nidhi Singh; Jiping Wang; Ke Chen; Yinzhi Lang; Jieqiang Zhou; Neera Kadiyala; Fiorella Krapp; Egon A. Ozer; Alan R. Hauser; Jian Li; Jürgen B. Bulitta; Zackery P. Bulman

doi:10.1128/AAC.00692-21

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

Yanqin Huang, Karol Sokolowski, Amisha Rana, Nidhi Singh, Jiping Wang, Ke Chen, Yinzhi Lang, Jieqiang Zhou, Neera Kadiyala, Fiorella Krapp, Egon A. Ozer, Alan R. Hauser, Jian Li, Jürgen B. Bulitta, Zackery P. Bulman^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

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.

Original language	English (US)
Article number	e00692-21
Journal	Antimicrobial agents and chemotherapy
Volume	65
Issue number	9
DOIs	https://doi.org/10.1128/AAC.00692-21
State	Published - Sep 2021

Funding

The project was funded in part by the Chicago Biomedical Consortium with support from the Searle Funds at The Chicago Community Trust (to Z.P.B. and A.R.H.). This project has also been funded in part by the National Institutes of Health (NIH), under Grant KL2TR002002 (to Z.P.B.). The bioanalysis of this study was supported by R01AI136803 (to J.B.B.). The content of the manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. J.L. is an Australian National Health and Medical Research Council Principal Research Fellow.

Keywords

Aminoglycoside-modifying enzymes
Aminoglycosides
Antimicrobial combinations
Carbapenemase
KPC
Klebsiella

ASJC Scopus subject areas

Pharmacology
Pharmacology (medical)
Infectious Diseases

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1128/AAC.00692-21

Cite this

Huang, Y., Sokolowski, K., Rana, A., Singh, N., Wang, J., Chen, K., Lang, Y., Zhou, J., Kadiyala, N., Krapp, F., Ozer, E. A., Hauser, A. R., Li, J., Bulitta, J. B., & Bulman, Z. P. (2021). Generating genotype-specific aminoglycoside combinations with ceftazidime/Avibactam for KPC-Producing Klebsiella pneumoniae. Antimicrobial agents and chemotherapy, 65(9), Article e00692-21. https://doi.org/10.1128/AAC.00692-21

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title = "Generating genotype-specific aminoglycoside combinations with ceftazidime/Avibactam for KPC-Producing Klebsiella pneumoniae",

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.",

keywords = "Aminoglycoside-modifying enzymes, Aminoglycosides, Antimicrobial combinations, Carbapenemase, KPC, Klebsiella",

author = "Yanqin Huang and Karol Sokolowski and Amisha Rana and Nidhi Singh and Jiping Wang and Ke Chen and Yinzhi Lang and Jieqiang Zhou and Neera Kadiyala and Fiorella Krapp and Ozer, {Egon A.} and Hauser, {Alan R.} and Jian Li and Bulitta, {J{\"u}rgen B.} and Bulman, {Zackery P.}",

year = "2021",

month = sep,

doi = "10.1128/AAC.00692-21",

language = "English (US)",

volume = "65",

journal = "Antimicrobial agents and chemotherapy",

issn = "0066-4804",

publisher = "American Society for Microbiology",

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Huang, Y, Sokolowski, K, Rana, A, Singh, N, Wang, J, Chen, K, Lang, Y, Zhou, J, Kadiyala, N, Krapp, F, Ozer, EA , Hauser, AR, Li, J, Bulitta, JB & Bulman, ZP 2021, 'Generating genotype-specific aminoglycoside combinations with ceftazidime/Avibactam for KPC-Producing Klebsiella pneumoniae', Antimicrobial agents and chemotherapy, vol. 65, no. 9, e00692-21. https://doi.org/10.1128/AAC.00692-21

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T1 - Generating genotype-specific aminoglycoside combinations with ceftazidime/Avibactam for KPC-Producing Klebsiella pneumoniae

AU - Huang, Yanqin

AU - Sokolowski, Karol

AU - Rana, Amisha

AU - Singh, Nidhi

AU - Wang, Jiping

AU - Chen, Ke

AU - Lang, Yinzhi

AU - Zhou, Jieqiang

AU - Kadiyala, Neera

AU - Krapp, Fiorella

AU - Ozer, Egon A.

AU - Hauser, Alan R.

AU - Li, Jian

AU - Bulitta, Jürgen B.

AU - Bulman, Zackery P.

PY - 2021/9

Y1 - 2021/9

N2 - 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.

AB - 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.

KW - Aminoglycoside-modifying enzymes

KW - Aminoglycosides

KW - Antimicrobial combinations

KW - Carbapenemase

KW - KPC

KW - Klebsiella

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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